Genetic and Clinical Characteristics of Japanese Cystinuria with Exon and Exon-Intron Boundary Variants

Genetic and Clinical Characteristics of Japanese Cystinuria with Exon and Exon-Intron Boundary Variants | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Genetic and Clinical Characteristics of Japanese Cystinuria with Exon and Exon-Intron Boundary Variants Shinichi Sakamoto, Yukio Naya, Junryo Rii, Kazumi Taguchi, Masaaki Fujimura, and 17 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4889642/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 26 Sep, 2025 Read the published version in Scientific Reports → Version 1 posted 16 You are reading this latest preprint version Abstract Cystinuria is the most common genetic cause of urinary stones. Defect in SLC3A1 / SLC7A9 genes coding cystine transporter proteins rBAT/b 0,+ AT will cause Cystinuria. The current work analyzed the clinical and genetics characteristics of Japanese Cystinuria patients. In total, 101 Cystinuria patients were studied. Clinical phenotypes were defined, and genetic analysis of SLC3A1 and SLC7A9 by next-generation sequence was performed. Excretion of urine cystine were determined by twenty-four hours urine analysis. The median age of presentation was 17 years old. In total, 51 different mutant variant alleles were identified (22 and 28 mutant variants in SLC3A1 and SLC7A9 , respectively), including 28 novel variants. The p.pro482Leu (c.1445C > T) variant in SCL7A9 was predominantly found in 73 patients. Variants in exon-intron boundaries were identified in 6 cases. The patient with homozygote intron (exon-intron boundary) variant in SCL7A9 presented a severe phenotype with significant loss of mRNA expression. Inclusion of exon and exon-intron boundary variants reduced the number of cases that did not fit autosomal recessive inheritance from 14–9%. Predominance of p.pro482Leu (c.1445C > T) variant in SCL7A9 was a unique characteristic of Japanese Cystinuria. Current data may provide a rationale for the inclusion of exon-intron boundary variants in genomic classification. Biological sciences/Genetics/Genome/Genetic variation Health sciences/Nephrology/Kidney diseases/Renal calculi Cystinuria Urinary Stone Genetic variant Germline variant Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Cystinuria (OMIM 220100) is a most common inherited urinary stone disease found in 1–2% of overall kidney stones. In the general population, the prevalence of Cystinuria was reported to be 1/15000 to 1/50000 1 . Although the prevalence rate of Cystinuria is low, the affected patients will suffer recurrent urinary stones from childhood and may undergo a series of surgeries, which will damage renal function and quality of life. It is essential to obtain the diagnosis at an early age and early stage of urinary stones. Cystinuria is caused by a pathogenic variants in two genes; SLC3A1 (OMIM 104614) encodes an rBAT (a single transmembrane protein), and SLC7A9 (OMIM 604144) encodes b 0,+ AT (a twelve transmembrane protein) 2 – 6 . rBAT and b 0,+ AT form a dimer linked by a disulfide bond. B 0,+ AT form the channel which transports dibasic amino acids (cystine, lysine, arginine, and ornithine) into the cell with the exchange of neutral amino acids. rBAT contains the multiple glycosylation sites at the extracellular domain. Interaction of b 0,+ AT is required for the rBAT to be fully glycosylated and properly folded and stably expressed at the cell membrane 2 – 6 . We have reported the role of carboxyl-terminal of b 0,+ AT in controlling the trafficking of the rBAT- b 0,+ AT from the endoplasmic reticulum (ER) to Golgi complex and thus control the full glycosylation of the rBAT protein 7 . Strologo et al. proposed the genome-based cystinuria classification 8 . The genotypes were classified, such as Type A, due to two variants of SLC3A1 ; type B, due to two variants of SLC7A9 ; and type AB, with one variant on each of the above-mentioned genes. However, Rhodes et al. reported that over thirty percent of the Cystinuria patients in the United Kingdom only possessed a single variant or even no variant, who will not fit into the genotypes previously proposed which will fit into the autosomal recessive inheritance 9 , 10 . Thus, it is of need to establish the genomic classification which will cover the unfit cases of genotype in Cystinuria. Previously, we have been studied Japanese Cystinuria since 1980’s and in 2006, we identified the presence of a unique variant; P482L is located at the carboxyl terminus end of B 0,+ AT among Japanese Cystinuria patients 1 , 11 – 15 . The P482L variant caused a severe functional defect of the Cystine transporter, which was found in over 80% of Japanese Cystinuria patients 1 . The high prevalence of the P482L variant had never been reported elsewhere. The prevalence of P482L variant among Cystinuria patients was reported 1/8 in South Korea 16 , 1/73 in the United Kingdom 10 , while no report in China 17 . Because of a distinct genotype in Japanese Cystinuria patients, a distinct clinical feature was also expected. Our previous genetic study of Cystinuria was based on exon lesion with sanger sequence. However, in recent years, a number of effects of the exon intron boundary on mRNA splicing have been reported. And also, there may a variant that could be missed by the sanger sequence. In order to precisely understand the genomic feature of Japanese Cystinuria, here we studied the genomic characteristics of 101 Japanese Cystinuria patients by next generation sequencing including exon-intron boundaries. Results Clinical Features In total, 101 patients diagnosed with Cystinuria were identified comprising 36 (35.6%) women and 65 (64.4%) men. All patients were Japanese. A positive family history of Cystinuria was documented in 29(28.7%) of patients;19(18.8%) patients had only one generation affected (siblings), 10(9.9%) patients had two generations affected. The median age at first presentation of stone symptom was 17 years old (range =0–58 years old) with a median age of 17.0 years old in the male and 16.5 years old in the female. The proportion of onset age for less than ten years, teenage, the 20s and 30s, and over were 38%, 24%, 25%, and 13%, respectively(Table 1). Genetic Analysis Genetic analysis was performed in all 101patients. At least two distinct genetic variants were detected in 93 patients, while eight patients only had a single variant. All the patients had at least one variant. Variants in SLC3A1 were identified in 18 patients, and variants in SLC7A9 were identified in 88 patients. Variants in both SLC3A1 and SLC7A9 were identified in 5 patients. Overall, 50 distinct variants were identified in SLC3A1 and SLC7A9 (Table 2 and 3). Among 22 variants identified in SLC3A1 , 14 variants were unreported (novel) variant (Table 2). Among 28 variants identified in SLC7A9 , 15 variants were unreported (novel) variants (Table 3). In SLC3A1 , 13 missense variants were identified, followed by four frameshifts and two splice-site variants, and one nonsense variant (Figure 1A). The most frequent variant in SLC3A1 was p.Val83Ala (c.5487T>C), which was found in 3 patients (3.0%), followed by Exon 10 deletion and p.Asn442fs. (c.1323dupT), which were found in 2 patients (2.0%) (Figure1A, Table 2). In SLC7A9 , 24 missense variants were identified, followed by three splice site and frameshift variants. One nonsense and one initial codon variant were also found (Figure 1B). The most frequent variant in SLC7A9 was p.pro482Leu (P482L)(c.1445C>T), which was found in 73 patients (72.7%)(43 homozygous and 30 heterozygous), followed by p.Val340fs (c.1017delA), which was found in 9 patients (8.9%)(1 homozygous and eight heterozygous) and p.Asn227Asp (c.679A>G), which was found in 4 patients (4.0%)(4 heterozygous)(Figure 1B, Table 3). Location of variants Regarding the location of the variants, all the variants in SLC3A1 were located at the extracellular domain except for p.Ala95Thr (c.313A>G) and p.Ile105Val (c.313A>G), which were located in the transmembrane domain of rBAT (Figure 2A). For the SLC7A9 , the most common variant, P482L, was located at the carboxyl terminus, while p.Met1Thr (c.2T>C) was located in the N-terminus of b 0,+ AT. Other variants were located at either transmembrane domain (14 variants), cytoplasmic loop (8 variants), or extracellular loop (5 variants) (Figure 2B). Genome-Phenotype Association Amount of urine cystine for the patients who have variant in SLC3A1 , SCL7A9 and SLC3A1/SLC7A9 were 1357.15, 1815.45 and 1434(µ mol/ day), respectively (Table 4). Regarding genotype, 12 patients (11.9%) were type AA and 76 patients (75.2%) were type BB, while one patient (1.0%) were type AAB and four patients (4.0%) were type ABB (Figure 3A). Genotype-Phenotype Association Amount of urine cystine for type AA, BB, AAB/BBA, A and B were 1230.6, 1815.45, 1434, 3034.6 and 1968.8, respectively. No significant difference in the amount of urine cystine was observed between genotypes (Figure 3B, Table 4). Age of onset for type AA, BB, AAB/BBA, and B were 13, 16, 27, and 13.5, respectively. No significant difference in the age of onset was observed between genotypes (Figure 3C). Genotype-Phenotype association based on P482L variant in SLC7A9. Regarding P482L variant in SLC7A9 , 43 patients (42.6%) had homozygote variants, 26 (25.7%) patients had compound heterozygote variants, four patients (4.0%) had single heterozygote variant and 28 patients (27.7%) had no P482L variant (Figure 4A). Amount of urine cystine for the patients of homozygote P482L variant, compound heterozygote P482L variant, single P482L variant and no P482L variant were 1705.2,2359.3, 1280.8, and 1483.7(µ mol/ day), respectively. No significant difference in the amount of urine cystine was observed between P482L based genotypes (Figure 4B, Table 4). Age of onset for type P482L homo, compound P482L hetero, none P482L were 20,10 and 16, respectively. No significant difference in the age of onset was observed based on the P482L variant classification (Figure 4C). Variants in exon-intron boundary Since variants in the exon-intron boundaries are responsible for the splicing error of the mRNA, we also study the variant in the exon-intron boundary. Overall, six exon-intron boundary variants were identified in six patients (Table 5). Among two patients without any variant in exon, one patient had homozygote variant (c.1224+3A>C) (classified as Type BB), and the other patient had heterozygote variant (c.1399+4_1399+7delAGTA) in exon-intron boundary (classified as Type B) (Table 5). All six patients who possessed exon-intron boundary variant resulted in the reclassification of the genotype (Table 5). The patients who had intron-exon boundary variants showed a relatively higher amount of cystine (3214.8 µmol/day) compared to those of patients who had exon variants (1705.4 µmol/day) (Table 6). In the case with homozygote c.1224+3A>C variant, we have studied the mRNA expression of the SLC3A1 and SLC7A9 . The male patient had first symptoms of kidney stone at the age of 3. His father was also affected by Cystinuria. At the age of 28, the patient consulted the hospital due to the left back pain. Computed tomographic scanning showed left staghorn calculus (Figure 5A). Based on the genomic analysis, the location of the variant was three sequences at the boundary of the exon 11(Figure 5B). No variant in exon was identified. The patient had a high amount of urinary cystine (3311.6 µmol/day) along with a high amount of lysine, ornithine, and arginine (Figure 5B). mRNA expression of the renal tissue showed a significant loss of SLC7A9 expression compare to that of SLC3A1 by RNA sequence (Figure 5C). Based on the genotype cover exon and exon-intron boundary, the case that did not fit the genotype of autosomal recessive inheritance reduced to 9 cases from 14 cases out of 101 cases (Figure 5E). Cases with a single variant When the Exon Intron boundary was included for the genotype, most of the cases had more than two variants, but eight cases had only one variant. Seven cases had variants in the Exon region and one in the Intron region. The median cystine concentration of the case with a single variant was 2501.7 (µmol/day), which was above the median cystine concentration of whole cohort of 1745.7 (µmol/day) (Table S1). Roots of Cystinuria patients We also study the origin of Cystinuria patients. 77% of patients are from the Kanto area (central region), where Tokyo and Chiba prefectures are located. 8% of patients are from the Kansai area (middle west), where Osaka prefectures is located. 7% of patients are from the Tokai area (middle south), where Aichi prefecture is located. No patient from the Tohoku area (north) was identified in this study (Figure S1A). Related to the percent of P482L variant, 100% of patients possessed P482L variant from Hokuriku (middle north), Kyusyu (far west), and Shikoku area (south west island). 76% and 57% of patients possessed P482L variant from Kanto (Tokyo and surrounding area) and Tokai area (middle south), respectively, while 37.5% from the Kansai area (middle west). No patients from Hokkaido area (northern island) possessed P482L variant (Figure S1 6B). The brief location of the region was illustrated in Figure S1C. Discussion Cystinuria is the most common genetic related kidney stones that is responsible for 1% of kidney stones 18 , 19 . Since Japan is geographically isolated by the ocean and even conducted a national isolation policy in the past during the Edo era (in 1636–1854), the development of genetic characteristics can be different from the rest of the countries. Current data described the unique genotype and phenotype characteristics of Japanese Cystinuria patients that are distinct from those of European and even Asian patients, such as presence of P482L variant and predominance of Type BB in genomic subtype. Furthermore, the current data is the first large genomic analysis using NGS covering the sequence of Exon and Exon-Intron boundary in Asian Cystinuria patients. Among Japanese Cystinuria patients, 73 out of 101 patients possessed P482L variant. Based on the common genome database (genome AD https://gnomad.broadinstitute.org/ ), the distribution of P482L variant in SLC7A9 among the global population is rare. P482L was not found in African, Latino, Ashkenazi Jewish, and European (Finish). Even for Asians, the allele frequency of P482L for south Asian and East Asian are 0.00006533 and 0.00005012, respectively. Among the previous Asian study of Cystinuria, only 1 out of 8 cystinuria patients possessed P482L(heterozygote) in south Korean 20 , while no P482L was identified in Chinese 17 . The P482L variant is located at the carboxyl terminus (C-terminus) end of b 0,+ AT, which causes severe transporter defect comparative to those of frameshift and stop codon variant 1 . Our previous study identified the "VPP" motif at the carboxyl terminus of b 0,+ AT regulate the ER-Golgi trafficking and thus control glycosylation of rBAT protein 7 . The last P in the "VPP" motif represented the location of P482L variant. Since the location of P482L variant is the almost end of the C-terminus, we are speculating protein-protein interaction may be responsible for this functional defect, similar to the PDZ domain of URAT1 21 . Related to the genotype classification, the distribution of Type BB was found in 76%, while Type AA was only found in 12% of patients in the current Japanese study. In the UK study, Type AA is dominant (36%), followed by Type BB (26%). In the Chinese Study, 37.5% (3 out of 8) were Type AA, and 25% (2 out of 8) were Type BB. In a Korean study, 50% (4 out of 8) of patients were Type AA, and only one patient (12.5%) was type BB. These data indicated the global trends of SLC3A1 variant in European and even Asian Cystinuria patients. Thus, the predominance of Type BB genotype found in Japanese Cystinuria patients seems to be unique characteristics. Beside SLC3A1 and SLC7A9 , novel cystine transporter, AGT1 was identified 22 . However, so far, no pathogenic variants were reported 23 . In a UK study, patients who have a variant in SLC3A1 (Type A or AA) demonstrated a significantly lower level of lysine, arginine, and ornithine, but not cystine compare to those of other patients 10 . Another study from the UK presented no difference in the clinical parameter between Type AA and Type BB. Furthermore, patients with a single mutated allele demonstrated similar disease severity compare to those of 2 mutated alleles 9 . In the current study, no difference in the severity of Cystinuria, such as urine cystine and age of onset, were observed based on the gene of variant (between SLC3A1 and SLC7A9 ), genotype (between type AA and type BB), and the number of mutated alleles(between single and two variant alleles). The difference in the clinical phenotype may be derived from a wide difference in the basal genome variants, in which we found 14 novel variants (total of 28 variants) in SLC3A1 and SLC7A9 , respectively. Recent evidence indicates the variant in the exon-intron boundary sequence resulted in the splicing error of the mRNA 24 . About 9% of all variants reported in the Human Gene Mutation Database (HGMD) are splicing variants 24 . In general, variants in canonical acceptor and donor sites affect the strongly conserved sequences that define exon-intron boundaries. The most typical variants affect + 1 and + 2 residues in the 5′ splice site and − 1 and − 2 residues in the 3′ acceptor splice site 24 . In the case of Neurofibromatosis type 1, c.1845 + 1G > A resulted in exon 15 and 16 skipping 25 . In the case of the c.1525-1G > A mutant variant in intron 9 of the CFTR gene resulted in the presence of three different mRNA isoforms 26 . Actually, it has been a missing piece of Cystinuria that up to 30% of patients did not fit into autosomal recessive inheritance category by exon variants 9 , 10 , which may be partially explained by variants in intron. In the current study, six exon-intron variants were identified, which resulted in the reclassification of the genotype. Among them, two patients previously identified no variant. One had homozygote, and the other had heterozygote exon-intron boundary variant. In the case with homozygote c.1224 + 3A > C variant in SLC7A9 , we have studied the mRNA expression of the SLC3A1 and SLC7A9 . Almost complete loss of SLC7A9 expression was observed by the exon-intron boundary variant. This data is, we believe, the first direct evidence of the significance of exon-intron boundary variant, which resulted in the loss of the transporter expression. Based on the genotype cover exon and exon-intron boundary, the cases that do not fit into the autosomal recessive inheritance category reduced to 9 cases from 14 cases. Based on the data, we propose genome classification based on the exon and exon-intron boundary. When looking at the origin of Cystinuria patients among the Japanese population, most of the patients were found from the middle (Kanto and Tokai) and west (Kansai) side of Japan. No patient was found on the northeast side of Japan (Tohoku Area) except one patient in Hokkaido (Northern Island). The current Japanese population is proposed to be the result of admixture between the early migrants (Jomon people) and later migrants (Yayoi people). Jomon people lived in the Northern and Southern parts of Japan, while Yayoi people lived in the central part of Japan. Few Cystinuria patients from the northeast side of Japan may indicate Japanese Cystinuria patients' roots may be derived from Yayoi people, rather than Jomon people 27 . We are currently studying the association of Japanese Cystinuria patients with Yayoi or Jomon people based on the genome-wide SNP data, especially related to the P482L variant in SLC7A9 . Further analysis will lead to the link between P482L variant and origin of Japanese people. The current manuscript contained several limitations. First, the data was obtained from Chiba university hospital with the collaboration with the hospitals from 15 different prefectures ranged from the northern part (Hokkaido) and the west side (Kyusyu) of Japan. Although data is obtained from a wide range of locations, our data missed some of the location in Japan. Second, the data is obtained in a retrospective manner. In order to improve the quality of the data, we are currently organizing the prospective registry system for kidney stone patients (CRYSTAL-J), including the patients with Cystinuria. Third, presence of splicing error induced by the exon-intron boundary variants has not fully been validated except one case presented. We are currently assessing the presence of splicing error due to the variants in exon-intron boundaries by in vitro transcription. Fourth, based on the previous evidence, about 25% of Cystinuria patients develop non-cystine stone 28 . It will be next project to assess the risk factors for the development of non-cystine stone among Japanese Cystinuria cohort. In conclusion, the current manuscript described the genomic and clinical signature of Japanese Cystinuria patients, which is distinct from not only European Cystinuria patients but also from Asian Cystinuria patients. Genotype classification may be updated based on not only exon but also exon-intron boundary variants. Methods Patient information Patients recruited to this study all had a clinical diagnosis of Cystinuria on the basis of clinical diagnosis of cystine stones from the southwest to northeast part of Japan between 2000 and 2020. Detailed clinical data were retrospectively collected. Demographics (age, sex and ethnicity) and age at the first stone events, treatment history, and urine biochemistry were collected. Definition of urine amino acids Cystine, lysine, arginine, and ornithine were measured by twenty-four hours urine sample. The amount of urine amino acids was determined by high performance liquid chromatography (HPLC) at SRL, Inc. (Hachioji, Tokyo, Japan). Statistical analysis Mann-Whitney's U test, ANOVA analysis, and the χ2 test were used for comparisons of two or three groups. Spearman's rank correlation coefficient was used to analyze the relationship between the two groups. Statistical computations were performed using JMP 11.0.0 (SAS Institute, NC, USA). P < 0.05 was considered significant. Genetic Analysis Genomic DNA was extracted from whole blood using the Blood & Cell Culture DNA Midi Kit (Qiagen, Hilden, Germany). Genetic variants of SLC3A1 (NM_000341.3) and SLC7A9 (NM_001126335.1) were analyzed by next-generation sequence of the protein-coding exons and their intron boundaries essentially as described previously 29 . In brief, libraries for the next generation sequence were made by a KAPA Hyper Plus Library Kit. Hybridization capture was made by predesigned hybridization capture probes for SLC3A1 and SLC7A9 purchased from IDT. The libraries were sequenced on an Illumina NextSeq500. Variant calling was done using GATKv4 ( https://gatk.broadinstitute.org/hc/en-us ). The variants thus detected by the next-generation sequencing were again confirmed by Sanger sequencing. The next-generation sequencing analysis was conducted at the Kazusa DNA Research Institute (Kisarazu, Chiba, Japan). Unreported (novel) variant was defined as the variant not reported on the previous publication. These gene variants are described with reference to the sequence of NM_000341.3 RNA sequencing The kidney tissue was obtained by biopsy. Total RNA from kidney biopsy sample was extracted using the RNeasy Mini Kit (Qiagen, Hilden, Germany). RNA sequencing libraries were prepared using a SureSelect Strand-Specific RNA Library Prep Kit (Agilent Technologies, Inc., Santa Clara, CA, USA). Sequencing was performed on a HiSeq 2500 system (Illumina, Santiago, CA, USA) in a 50-base single-end mode. TopHat (version 2.1.0; with default parameters) was used to map to the human reference genome (hg38). Then, gene expression levels were quantified using Cufflinks version 2.2.1; with default parameters) and are expressed as the number of fragments per kilobase of exon per million reads mapped (FPKM). Ethical Approval and Consent to Participate The present study was conducted in accordance with ethical standards that promote and ensure respect and integrity for all human subjects and the Declaration of Helsinki. This study was approved by the institutional review board of Chiba University Hospital (approval number 1050), Nagoya City University Hospital (approval number of 70-19-0018) and other participated hospitals and written informed consent was obtained from all patients. Declarations Conflict of interest The authors declare no competing financial interests. Funding information The present work was supported by 5th research grant from Japanese Society on Urolithiasis Research to S. Sakamoto, the Japan Agency for Medical Research and Development, the Initiative on Rare and Undiagnosed Diseases (IRUD) to T. Ichikawa and the Japan Agency for Medical Research and Development (AMED) (JP21ek0109549)to T. Ichikawa. Author Contribution YN and SS conceived and designed the experiments. JR, MM, SS, ST, NS, CI and YI analyzed the data. AA, AC, KW, MN, MF, YS, TU, TY, YK, YN, YY, KA, YI, MS, NA and TI supervised the study. AT, SH and KT provided the samples. Acknowledgement The authors thank Osamu Ohara (Kazusa DNA Research Institute, Kisarazu, Japan) for the NGS analysis and RNA sequence. The authors also thank Chiaki Hosaka for organizing the data. The author also thanks, Natsuko Kusama, Masako Takahashi, Hisayo Karahi, Keiko Yamazaki (Experimental assistant, Chiba University) for their support of this study. Data Availability The data was generated based on the funding from the Japanese Society on Urolithiasis Research (JSUR), the Initiative on Rare and Undiagnosed Diseases (IRUD) and the Japan Agency for Medical Research and Development (AMED). The data are available from the authors upon reasonable request and with the permission of the JSUR. 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A novel mutation in the neurofibromatosis type 1 (NF1) gene promotes skipping of two exons by preventing exon definition. J. Mol. Biol. 307 , 1261–1270. 10.1006/jmbi.2001.4561 (2001). Ramalho, A. S. et al. Transcript analysis of the cystic fibrosis splicing mutation 1525-1G > A shows use of multiple alternative splicing sites and suggests a putative role of exonic splicing enhancers. J. Med. Genet. 40 , e88. 10.1136/jmg.40.7.e88 (2003). Jinam, T. A. et al. Unique characteristics of the Ainu population in Northern Japan. J. Hum. Genet. 60 , 565–571. 10.1038/jhg.2015.79 (2015). Reinstatler, L. et al. Conversion from Cystine to Noncystine Stones: Incidence and Associated Factors. J. Urol. 200 , 1285–1289. 10.1016/j.juro.2018.07.047 (2018). Fujiki, R. et al. Assessing the Accuracy of Variant Detection in Cost-Effective Gene Panel Testing by Next-Generation Sequencing. J. Mol. Diagn. 20 , 572–582. 10.1016/j.jmoldx.2018.04.004 (2018). Tables Table 1. Demographic and clinical data Characteristic value number of patients (N) 101 Median age at presentation (years) (range) 17.0 (0-58) Less than 10 years/teen age/20s/30s and over 38/24/25/13(%) Male 17.0 (0-48) Female 16.5 (0-58) Sex: male (N=65)/ female (N=36) 64.4% Family Histroy (1st sibling/2nd sibling) 29% (19%/10%) Ethnicity: Japanese 100% Median age at follow-up (years) 33.0 (0.3-78.0) Median time from initial symptoms to follow-up (years) 14.0 (0.0-56.0) Cystine (μmol/day) 1745.7 (184.6 - 5303.4 ) Ornithine (μmol/day) 2044.3 (205.2 - 7471.7) Lysine (μmol/day) 8646.7 (536.9 - 36961.6) Arginine (μmol/day) 3334.2 (96.3 - 12096.0) Table 2. List of variants in SLC3A1 SLC3A1 Variant Type Variants Protein Sequence Homo/Hetero PT Number Exon Location 1 Missense c.283G>A* p.Ala95Thr Hetero 1 1 TM1 2 Missense c.313A>G* p.Ile105Val Hetero 1 1 TM1 3 Missense c.470T>C* p.Ile157Thr Hetero 1 2 Extra 4 Missense c.548T>C* p.Val183Ala Hetero 3 2 Extra 5 Missense c.659A>G* p.His220Arg Hetero 1 3 Extra 6 Missense c.763T>A * p.Trp255Arg Hetero 1 3 Extra 7 Missense c.989A>C* p.Gln330Pro Hetero 1 5 Extra 8 Missense c.1037T>C p.Leu346Pro Hetero 1 6 Extra 9 Missense c.1323C>G* p.Pro441Arg Hetero 1 7 Extra 10 Missense c.1334T>C p.Ile445Thr Hetero 1 8 Extra 11 Missense c.1742T>G* p.Val581Gly Hetero 1 10 Extra 12 Missense c.1772G>A * p.Arg591Lys Hetero 1 10 Extra 13 Missense c.2017T>C p.Cys673Arg Hetero 1 10 Extra 14 Nonsense c.1113C>A p.Tyr371X Hetero 1 6 Extra 15 Nonsense c.1328G>A* p.Trp443X Homo 1 7 Extra 16 Frameshift c.1323dupT* p.Asn442fs Hetero 2 7 Extra 17 Frameshift c.1820delT p.Leu607fs Hetero 1 10 Extra 18 Frameshift c.1820delT p.Leu607fs Homo 1 10 Extra 19 Frameshift c.1898_1899insAT* p.Asp634fs Homo 1 10 Extra 20 Splice site c.1500+1G>A Hetero 1 8+1 intro Extra 21 Splice site c.1617+1_1617+2dupGT* Hetero 1 9+1+2 intron Extra 22 Deletions Ex10 deletion Homo 2 10 Extra Missense: missense variant, Frameshift: frame shift variant, Nonsense: nonsense variant, Frameshift: frameshift variant, Splice site: splice site variant (exon-intron boundary variant), TM: transmembrane domain, Extra: extracellular domain, new: novel variant not reported previously. These gene variants are described with reference to the sequence of NM_000341.3 Table 3. List of variants in SLC7A9 SLC7A9 Variant Type Variants Protein Sequence Homo/Hetero PT Number Exon Location 1 Missense c.2T>C new p.Met1Thr Hetero 1 2 Cytoplasmic 2 Missense c.206G>A p.Trp69X Hetero 2 3 TM2 3 Missense c.209C>T p.Ala70Val Hetero 1 3 TM2 4 Missense c.217G>A p.Gly73Arg Hetero 1 3 TM2 5 Missense c.308C>T new p.Ala103Val Hetero 1 4 TM3 6 Missense c.511C>T p.Arg171Trp Hetero 1 5 Cytoplasmic Loop2 7 Missense c.583G>A p.Gly195Arg Hetero 2 5 TM5 8 Missense c.650C>G new p.Ser217Cys Hetero 1 6 TM6 9 Missense c.671C>T p.Ala224Val Hetero 1 6 TM6 10 Missense c.679A>G p.Asn227Asp Hetero 4 6 TM6 11 Missense c.698A>G new p.Asp233Gly Homo/Hetero 1/1 6 Cytoplasmic Loop3 12 Missense c.829G>A new p.Val277Met Hetero 1 7 Extra Loop4 13 Missense c.886C>G new p.Arg296Gly Hetero 1 9 Extra Loop4 14 Missense c.968C>T new p.Thr323Ile Hetero 1 9 Cytoplasmic Loop4 15 Missense c.974G>T new p.Gly325Val Hetero 1 9 Cytoplasmic Loop4 16 Missense c.992C>T p.Ala331Val Homo 1 10 Cytoplasmic Loop4 17 Missense c.998G>A p.Arg333Gln Hetero 2 10 Cytoplasmic Loop4 18 Missense c.1061C>A p.Ala354Asp Hetero 5 10 TM9 19 Missense c.1124T>C new p.Val375Ala Homo 1 11 TM10 20 Missense c.1166C>T p.Thr389Met Hetero 1 11 TM10 21 Missense c.1336A>C new p.Ser446Arg Hetero 1 12 TM12 22 Missense c.1445C>T p.pro482Leu Homo/Hetero 43/30 13 Cytoplasmic 23 Frameshift c.611_612delCA new p.thr204fs Hetero 1 6 Extra Loop3 24 Frameshift c.1017delA p.Val340fs Homo/Hetero 1 10 Cytoplasmic Loop4 25 Splice site c.873+2dupT new Hetero 1 Intron(Exon 8+2) Extra Loop4 26 Splice site c.1074+1G>A new Hetero 1 Intron(Exon 10+1) Extra Loop5 27 Splice site c.1224+3A>C new Homo 1 Intron(Exon 11+3) Cytoplasmic Loop5 28 Splice site c.1399+4_1399+7delAGTA Hetero 1 Intron(Exon 12+4-7) TM12 Missense: missense variant, Frameshift: frame shift variant, Nonsense: nonsense variant, Frameshift: frameshift variant, Splice site: splice site variant (exon-intron boundary variant), TM: transmembrane domain, Extra: extracellular domain, new: novel variant not reported previously. These gene variants are described with reference to the sequence of NM_000341.3 Table 4. Aminoacid concentration based on Genes, Genotype and P482L variant Urine Aminoacids: : µmol/day Cystine Ornithine Lysine Arginine Median Range Median Range Median Range Median Range Based on Genes SLC3A1 1357.2 (186.9-3117.9) 1692.6 (861.3-3848.1) 7051.8 (5307.9-12456.4) 2682.7 (323.4-4590.5) SLC7A9 1832.2 (184.6-5303.4) 2020.15 (205.2-7471.7) 8787.8 (536.9-36961.6) 3334.2 (96.3-12096) SLC3A1/SLC7A9 1434 (1037.3-3722.9) 3174.4 (2302.1-4316.8) 8144 (1300.2-13826.2) 3495.9 (2269-5996.8) Based on Genotype AA 1230.6 (186.9-3117.9) 1355.8 (861.3-3848.1) 5631.6 (5307.9-9223.1) 1002.9 (323.4-4590.5) BB 1815.45 (184.6-5303.4) 2036.8 (205.2-7417.7) 8858.5 (536.9-36961.6) 3334.2 (150.4-12096) AAB/BBA 1434 (1037.3-3722.9) 3174.4 (2302.1-4316.8) 8144 (1300.2-13826.2) 3495.9 (2269-5996.8) A 3034.6 (3034.6-3034.6) 2029.4 (2029.4-2029.4) 12456.4 (12456.5-12456.5) 4425.4 (4425.4-4425.4) B 1968.8 (592.8-4094.2) 1616.4 (278.3-2843) 8576.3 (3038.4-10211.1) 555.9 (96.3-5037.6) Based on P482L P482L Homo 1705.15 (184.6-4368) 2195.6 (205.2-4316.8) 8858.5 (536.9-17412) 3423.4 (150.4-6531) P482L compound hetero 2359.3 (851-5303.4) 2183.1 (716-7471.7) 8970.1 (2968.4-36961.6) 3875.3 (1416.6-12096) P482L single Hetero 1280.8 (592.8-1968.8) 1560.65 (278.3-2843) 5807.4 (3038.4-8576.3) 2567 (96.3-5037.6) None P482L 1483.7 (186.9-4094.2) 1822.9 (845.4-5497.2) 8594.5 (2411.5-16476.1) 1729.4 (323.4-9512.9) Table 5. List of cases with Exon-Intron boundary variants SLC3A1 SLC7A9 Genotype Variants Variants Exon only Exon/Exon-Intron boundary 1 T204fs c.611_612delCA (hetero) c.873+2dupT (hetero)* Type B Type BB 2 c.1224+3A>C (homo)* No mutation Type BB 3 c.1399+4_1399+7delAGTA (hetero)* No mutation Type B 4 Y371Ter(hetero)C1113A c.1500+1G>A (hetero)* Type A Type AA 5 P441R(hetero)C1322G c.1617+1_1617+2dupGT (hetero)* Type A Type AA 6 P482L(hetero)C1445T c.1074+1G>A (hetero)* Type B Type BB * Exon-Intron boundary (Splice site) variant Table 6. Urine aminoacid concentration based on Exon/Exon-intron boundary variants Urine Aminoacids: : µmol/day Cystine Ornithine Lysine Arginine Median Range Median Range Median Range Median Range Exon variant 1705.4 (184.6-5303.4) 2044.3 (205.2-7471.7) 8538.6 (536.9-36961.6) 3512.6 (96.3-12096) Exon-intron boundary variant 3214.8 (1025.6-4094.2) 2732.3 (845.4-3922.7) 9134.9 (2411.5-10211.1) 1169.5 (555.9-4362.4) Additional Declarations No competing interests reported. Supplementary Files 20240807SupportingInfo.docx Cite Share Download PDF Status: Published Journal Publication published 26 Sep, 2025 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Revision requested 25 Nov, 2024 Reviews received at journal 23 Nov, 2024 Reviews received at journal 20 Nov, 2024 Reviewers agreed at journal 14 Nov, 2024 Reviewers agreed at journal 13 Nov, 2024 Reviews received at journal 21 Oct, 2024 Reviewers agreed at journal 16 Oct, 2024 Reviewers agreed at journal 15 Oct, 2024 Reviewers agreed at journal 11 Sep, 2024 Reviews received at journal 05 Sep, 2024 Reviewers agreed at journal 26 Aug, 2024 Reviewers invited by journal 25 Aug, 2024 Editor assigned by journal 25 Aug, 2024 Editor invited by journal 24 Aug, 2024 Submission checks completed at journal 24 Aug, 2024 First submitted to journal 09 Aug, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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02:53:16","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4889642/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4889642/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-025-14240-4","type":"published","date":"2025-09-26T15:56:59+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":66770573,"identity":"31a6a348-fbc4-4a73-9d6d-509466dc9ef1","added_by":"auto","created_at":"2024-10-16 10:07:46","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":198887,"visible":true,"origin":"","legend":"\u003cp\u003eDistribution of variant in \u003cem\u003eSLC3A1\u003c/em\u003e and SCL7A9\u003c/p\u003e\n\u003cp\u003eIn \u003cem\u003eSLC3A1\u003c/em\u003e, 13 missense variants were identified, followed by four frameshifts and two splice-site variants, and one nonsense variant. The most frequent variant in \u003cem\u003eSLC3A1\u003c/em\u003e was p.Val183Ala (c.5487T\u0026gt;C), followed by Exon 10 deletion and p.Asn442fs. (c.1323dupT). In \u003cem\u003eSLC7A9\u003c/em\u003e, 24 missense variants were identified, followed by three splice site and frameshift variants. One nonsense and one initial codon variant were also found. The most frequent variant in \u003cem\u003eSLC7A9\u003c/em\u003e was p.pro482Leu (c.1445C\u0026gt;T), which was found in 73 patients (43 homozygous and 30 heterozygous). Red column indicated novel variant.\u003c/p\u003e","description":"","filename":"Picture1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4889642/v1/4d3e49b0d5bb5204098acb38.jpg"},{"id":66769123,"identity":"a89c3cf3-35e0-4e41-99c9-5dd3d72eb66a","added_by":"auto","created_at":"2024-10-16 09:51:46","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":149687,"visible":true,"origin":"","legend":"\u003cp\u003eLocation of variants in rBAT (\u003cem\u003eSLC3A1\u003c/em\u003e) and b\u003csup\u003e0,+\u003c/sup\u003eAT (\u003cem\u003eSLC7A9\u003c/em\u003e) in exon and protein domain\u003c/p\u003e\n\u003cp\u003eSchematic diagram of rBAT and b\u003csup\u003e0,+\u003c/sup\u003eAT. rBAT protein has a single transmembrane domain (Blue) with a long extracellular domain with cytoplasmic domain encoded by ten exons(A). b\u003csup\u003e0,+\u003c/sup\u003eAT protein has 12 transmembrane domains with a cytoplasmic domain at N-terminus and C-terminus. p.pro482Leu variant is located at the C-terminus end(B).\u003c/p\u003e","description":"","filename":"Picture2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4889642/v1/4ff45c82dccbd48b9676e869.jpg"},{"id":66769126,"identity":"88dea239-f18f-4437-8db5-b12b7e83a031","added_by":"auto","created_at":"2024-10-16 09:51:46","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":109364,"visible":true,"origin":"","legend":"\u003cp\u003eDistribution of Cystinuria genotype\u003c/p\u003e\n\u003cp\u003eDistribution of genotype represented predominance of type BB followed by type AA and Type B (A). Urine cystine based on the genotype (B). Age of onset based on the genotype (C)\u003c/p\u003e","description":"","filename":"Picture3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4889642/v1/339f2b78bd93c119c2d11236.jpg"},{"id":66770126,"identity":"130dc814-5fc1-4756-a74c-d8d4984b72ec","added_by":"auto","created_at":"2024-10-16 09:59:46","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":97251,"visible":true,"origin":"","legend":"\u003cp\u003eDistribution of P482L variant\u003c/p\u003e\n\u003cp\u003eDistribution of P482L variant represented predominance of homozygote variant (n=43) followed by compound heterozygote variant (n=26) (A). Urine cystine based on P482L variant (B). Age of onset based on P482L variant (C).\u003c/p\u003e","description":"","filename":"Picture4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4889642/v1/1708f2591c79dbc54416e163.jpg"},{"id":66769127,"identity":"cbb1adbd-2a95-4bce-9834-0172c9d1cbd8","added_by":"auto","created_at":"2024-10-16 09:51:46","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":109611,"visible":true,"origin":"","legend":"\u003cp\u003eThe case with homozygote exon-intron boundary variant\u003c/p\u003e\n\u003cp\u003eThe CT image of the patient with left staghorn calculus (A). The case possessed c.1224+3A\u0026gt;C homozygote variant in \u003cem\u003eSLC7A9\u003c/em\u003e, which\u003cem\u003e \u003c/em\u003ewas located 3 bases into the intron from the exon-intron boundary (B). 24hour urine amino acids of the patient(C). mRNA expression of the \u003cem\u003eSCL3A1 \u003c/em\u003eand \u003cem\u003eSLC7A9 \u003c/em\u003egenes based on the RNA sequence (D). FPKM represent RNA expression based on the number of fragments per kilobase of exon per million reads mapped. Based on the genotype cover exon and exon-intron boundary, the cases that do not fit into the autosomal recessive inheritance category reduced to 9 cases from 14 cases (E).\u003c/p\u003e","description":"","filename":"Picture5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4889642/v1/b88646ae8b33e544be2dee39.jpg"},{"id":92430418,"identity":"ca410686-673f-4d85-83bd-cabe06c92a98","added_by":"auto","created_at":"2025-09-29 16:02:24","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2065989,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4889642/v1/ec3f4716-3de5-476f-8175-0beaa061f9d8.pdf"},{"id":66769128,"identity":"febfe924-cb2f-433a-be85-3e1b20e03e74","added_by":"auto","created_at":"2024-10-16 09:51:46","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":101833,"visible":true,"origin":"","legend":"","description":"","filename":"20240807SupportingInfo.docx","url":"https://assets-eu.researchsquare.com/files/rs-4889642/v1/183a5cd57423d650fc54b4a2.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Genetic and Clinical Characteristics of Japanese Cystinuria with Exon and Exon-Intron Boundary Variants","fulltext":[{"header":"Introduction","content":"\u003cp\u003eCystinuria (OMIM 220100) is a most common inherited urinary stone disease found in 1\u0026ndash;2% of overall kidney stones. In the general population, the prevalence of Cystinuria was reported to be 1/15000 to 1/50000\u003csup\u003e1\u003c/sup\u003e. Although the prevalence rate of Cystinuria is low, the affected patients will suffer recurrent urinary stones from childhood and may undergo a series of surgeries, which will damage renal function and quality of life. It is essential to obtain the diagnosis at an early age and early stage of urinary stones.\u003c/p\u003e \u003cp\u003eCystinuria is caused by a pathogenic variants in two genes; \u003cem\u003eSLC3A1\u003c/em\u003e (OMIM 104614) encodes an rBAT (a single transmembrane protein), and \u003cem\u003eSLC7A9\u003c/em\u003e (OMIM 604144) encodes b\u003csup\u003e0,+\u003c/sup\u003eAT (a twelve transmembrane protein)\u003csup\u003e\u003cspan additionalcitationids=\"CR3 CR4 CR5\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. rBAT and b\u003csup\u003e0,+\u003c/sup\u003eAT form a dimer linked by a disulfide bond. B\u003csup\u003e0,+\u003c/sup\u003eAT form the channel which transports dibasic amino acids (cystine, lysine, arginine, and ornithine) into the cell with the exchange of neutral amino acids. rBAT contains the multiple glycosylation sites at the extracellular domain. Interaction of b\u003csup\u003e0,+\u003c/sup\u003eAT is required for the rBAT to be fully glycosylated and properly folded and stably expressed at the cell membrane\u003csup\u003e\u003cspan additionalcitationids=\"CR3 CR4 CR5\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. We have reported the role of carboxyl-terminal of b\u003csup\u003e0,+\u003c/sup\u003eAT in controlling the trafficking of the rBAT- b\u003csup\u003e0,+\u003c/sup\u003eAT from the endoplasmic reticulum (ER) to Golgi complex and thus control the full glycosylation of the rBAT protein\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eStrologo et al. proposed the genome-based cystinuria classification\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. The genotypes were classified, such as Type A, due to two variants of \u003cem\u003eSLC3A1\u003c/em\u003e; type B, due to two variants of \u003cem\u003eSLC7A9\u003c/em\u003e; and type AB, with one variant on each of the above-mentioned genes. However, Rhodes et al. reported that over thirty percent of the Cystinuria patients in the United Kingdom only possessed a single variant or even no variant, who will not fit into the genotypes previously proposed which will fit into the autosomal recessive inheritance \u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. Thus, it is of need to establish the genomic classification which will cover the unfit cases of genotype in Cystinuria.\u003c/p\u003e \u003cp\u003ePreviously, we have been studied Japanese Cystinuria since 1980\u0026rsquo;s and in 2006, we identified the presence of a unique variant; P482L is located at the carboxyl terminus end of B\u003csup\u003e0,+\u003c/sup\u003eAT among Japanese Cystinuria patients\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan additionalcitationids=\"CR12 CR13 CR14\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. The P482L variant caused a severe functional defect of the Cystine transporter, which was found in over 80% of Japanese Cystinuria patients\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. The high prevalence of the P482L variant had never been reported elsewhere. The prevalence of P482L variant among Cystinuria patients was reported 1/8 in South Korea\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e, 1/73 in the United Kingdom \u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e, while no report in China\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. Because of a distinct genotype in Japanese Cystinuria patients, a distinct clinical feature was also expected.\u003c/p\u003e \u003cp\u003eOur previous genetic study of Cystinuria was based on exon lesion with sanger sequence. However, in recent years, a number of effects of the exon intron boundary on mRNA splicing have been reported. And also, there may a variant that could be missed by the sanger sequence. In order to precisely understand the genomic feature of Japanese Cystinuria, here we studied the genomic characteristics of 101 Japanese Cystinuria patients by next generation sequencing including exon-intron boundaries.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eClinical Features\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn total, 101 patients diagnosed with Cystinuria were identified comprising 36 (35.6%) women and 65 (64.4%) men. All patients were Japanese. A positive family history of Cystinuria was documented in 29(28.7%) of patients;19(18.8%) patients had only one generation affected (siblings), 10(9.9%) patients had two generations affected. The median age at first presentation of stone symptom was 17 years old (range =0\u0026ndash;58 years old) with a median age of 17.0 years old in the male and 16.5 years old in the female. The proportion of onset age for less than ten years, teenage, the 20s and 30s, and over were 38%, 24%, 25%, and 13%, respectively(Table 1). \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGenetic Analysis\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eGenetic analysis was performed in all 101patients. At least two distinct genetic variants were detected in 93 patients, while eight patients only had a single variant. All the patients had at least one variant. Variants in \u003cem\u003eSLC3A1\u0026nbsp;\u003c/em\u003ewere identified in 18 patients, and variants in \u003cem\u003eSLC7A9\u003c/em\u003e were identified in 88 patients. Variants in both SLC3A1 and \u003cem\u003eSLC7A9\u0026nbsp;\u003c/em\u003ewere identified in 5 patients. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOverall, 50 distinct variants were identified in \u003cem\u003eSLC3A1\u003c/em\u003e and \u003cem\u003eSLC7A9\u0026nbsp;\u003c/em\u003e(Table 2 and 3). Among 22 variants identified in \u003cem\u003eSLC3A1\u003c/em\u003e, 14 variants were unreported (novel) variant (Table 2). Among 28 variants identified in \u003cem\u003eSLC7A9\u003c/em\u003e, 15 variants were unreported (novel) variants (Table 3). In \u003cem\u003eSLC3A1\u003c/em\u003e, 13 missense variants were identified, followed by four frameshifts and two splice-site variants, and one nonsense variant (Figure 1A). The most frequent variant in \u003cem\u003eSLC3A1\u0026nbsp;\u003c/em\u003ewas p.Val83Ala (c.5487T\u0026gt;C), which was found in 3 patients (3.0%), followed by Exon 10 deletion and p.Asn442fs. (c.1323dupT), which were found in 2 patients (2.0%) (Figure1A, Table 2). In\u003cem\u003e\u0026nbsp;SLC7A9\u003c/em\u003e, 24 missense variants were identified, followed by three splice site and frameshift variants. One nonsense and one initial codon variant were also found (Figure 1B).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe most frequent variant in \u003cem\u003eSLC7A9\u0026nbsp;\u003c/em\u003ewas p.pro482Leu (P482L)(c.1445C\u0026gt;T), which was found in 73 patients (72.7%)(43 homozygous and 30 heterozygous), followed by p.Val340fs (c.1017delA), which was found in 9 patients (8.9%)(1 homozygous and eight heterozygous) and p.Asn227Asp (c.679A\u0026gt;G), which was found in 4 patients (4.0%)(4 heterozygous)(Figure 1B, Table 3). \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLocation of variants\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRegarding the location of the variants, all the variants in \u003cem\u003eSLC3A1\u003c/em\u003e were located at the extracellular domain except for p.Ala95Thr (c.313A\u0026gt;G) and p.Ile105Val (c.313A\u0026gt;G), which were located in the transmembrane domain of rBAT (Figure 2A). For the \u003cem\u003eSLC7A9\u003c/em\u003e, the most common variant, P482L, was located at the carboxyl terminus, while p.Met1Thr (c.2T\u0026gt;C) was located in the N-terminus of b\u003csup\u003e0,+\u003c/sup\u003eAT. Other variants were located at either transmembrane domain (14 variants), cytoplasmic loop (8 variants), or extracellular loop (5 variants) (Figure 2B).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGenome-Phenotype Association\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAmount of urine cystine for the patients who have variant in \u003cem\u003eSLC3A1\u003c/em\u003e, \u003cem\u003eSCL7A9\u0026nbsp;\u003c/em\u003eand \u003cem\u003eSLC3A1/SLC7A9\u003c/em\u003e were 1357.15, 1815.45 and 1434(\u0026micro; mol/ day), respectively (Table 4). Regarding genotype, 12 patients (11.9%) were type AA and 76 patients (75.2%) were type BB, while one patient (1.0%) were type AAB and four patients (4.0%) were type ABB (Figure 3A).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGenotype-Phenotype Association\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAmount of urine cystine for type AA, BB, AAB/BBA, A and B were\u0026nbsp;1230.6, 1815.45, 1434, 3034.6 and 1968.8, respectively.\u0026nbsp;No significant difference in the amount of urine cystine was observed between genotypes (Figure 3B, Table 4). Age of onset\u0026nbsp;for type AA, BB, AAB/BBA, and B were\u0026nbsp;13, 16, 27, and 13.5, respectively.\u0026nbsp;No significant difference in the age of onset was observed between genotypes (Figure 3C).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGenotype-Phenotype association based on P482L variant in \u003cem\u003eSLC7A9.\u003c/em\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRegarding P482L variant in \u003cem\u003eSLC7A9\u003c/em\u003e, 43 patients (42.6%) had homozygote variants, 26 (25.7%) patients had compound heterozygote variants, four patients (4.0%) had single heterozygote variant and 28 patients (27.7%) had no P482L variant (Figure 4A). Amount of urine cystine for the patients of homozygote P482L variant, compound heterozygote P482L variant, single P482L variant and no P482L variant were 1705.2,2359.3, 1280.8, and 1483.7(\u0026micro; mol/ day), respectively. No significant difference in the amount of urine cystine was observed between P482L based genotypes (Figure 4B, Table 4). Age of onset\u0026nbsp;for type P482L homo, compound P482L hetero, none P482L were\u0026nbsp;20,10 and 16, respectively.\u0026nbsp;No significant difference in the age of onset was observed based on the P482L variant classification (Figure 4C).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eVariants in exon-intron boundary\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSince variants in the exon-intron boundaries are responsible for the splicing error of the mRNA, we also study the variant in the exon-intron boundary. Overall, six exon-intron boundary variants were identified in six patients (Table 5). Among two patients without any variant in exon, one patient had homozygote variant (c.1224+3A\u0026gt;C) (classified as Type BB), and the other patient had heterozygote variant (c.1399+4_1399+7delAGTA) in exon-intron boundary (classified as Type B) (Table 5). All six patients who possessed exon-intron boundary variant resulted in the reclassification of the genotype (Table 5). The patients who had intron-exon boundary variants showed a relatively higher amount of cystine (3214.8 \u0026micro;mol/day) compared to those of patients who had exon variants (1705.4 \u0026micro;mol/day) (Table 6).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn the case with homozygote c.1224+3A\u0026gt;C variant, we have studied the mRNA expression of the \u003cem\u003eSLC3A1\u003c/em\u003e and \u003cem\u003eSLC7A9\u003c/em\u003e. The male patient had first symptoms of kidney stone at the age of 3. His father was also affected by Cystinuria. At the age of 28, the patient consulted the hospital due to the left back pain. Computed tomographic scanning showed left staghorn calculus (Figure 5A). Based on the genomic analysis, the location of the variant was three sequences at the boundary of the exon 11(Figure 5B). No variant in exon was identified. The patient had a high amount of urinary cystine (3311.6 \u0026micro;mol/day) along with a high amount of lysine, ornithine, and arginine (Figure 5B). mRNA expression of the renal tissue showed a significant loss of \u003cem\u003eSLC7A9\u003c/em\u003e expression compare to that of \u003cem\u003eSLC3A1\u0026nbsp;\u003c/em\u003eby RNA sequence (Figure 5C). Based on the genotype cover exon and exon-intron boundary, the case that did not fit the genotype of autosomal recessive inheritance reduced to 9 cases from 14 cases out of 101 cases (Figure 5E).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCases with a single variant\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWhen the Exon Intron boundary was included for the genotype, most of the cases had more than two variants, but eight cases had only one variant. Seven cases had variants in the Exon region and one in the Intron region. The median cystine concentration of the case with a single variant was 2501.7 (\u0026micro;mol/day), which was above the median cystine concentration of whole cohort of 1745.7 (\u0026micro;mol/day) (Table S1).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRoots of Cystinuria patients \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe also study the origin of Cystinuria patients. 77% of patients are from the Kanto area (central region), where Tokyo and Chiba prefectures are located. 8% of patients are from the Kansai area (middle west), where Osaka prefectures is located. 7% of patients are from the Tokai area (middle south), where Aichi prefecture is located. No patient from the Tohoku area (north) was identified in this study (Figure S1A). Related to the percent of P482L variant, 100% of patients possessed P482L variant from Hokuriku (middle north), Kyusyu (far west), and Shikoku area (south west island). 76% and 57% of patients possessed P482L variant from Kanto (Tokyo and surrounding area) and Tokai area (middle south), respectively, while 37.5% from the Kansai area (middle west). No patients from Hokkaido area (northern island) possessed P482L variant (Figure S1 6B). The brief location of the region was illustrated in Figure S1C.\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eCystinuria is the most common genetic related kidney stones that is responsible for 1% of kidney stones\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e,\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. Since Japan is geographically isolated by the ocean and even conducted a national isolation policy in the past during the Edo era (in 1636\u0026ndash;1854), the development of genetic characteristics can be different from the rest of the countries. Current data described the unique genotype and phenotype characteristics of Japanese Cystinuria patients that are distinct from those of European and even Asian patients, such as presence of P482L variant and predominance of Type BB in genomic subtype. Furthermore, the current data is the first large genomic analysis using NGS covering the sequence of Exon and Exon-Intron boundary in Asian Cystinuria patients.\u003c/p\u003e \u003cp\u003eAmong Japanese Cystinuria patients, 73 out of 101 patients possessed P482L variant. Based on the common genome database (genome AD \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://gnomad.broadinstitute.org/\u003c/span\u003e\u003cspan address=\"https://gnomad.broadinstitute.org/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e), the distribution of P482L variant in \u003cem\u003eSLC7A9\u003c/em\u003e among the global population is rare. P482L was not found in African, Latino, Ashkenazi Jewish, and European (Finish). Even for Asians, the allele frequency of P482L for south Asian and East Asian are 0.00006533 and 0.00005012, respectively. Among the previous Asian study of Cystinuria, only 1 out of 8 cystinuria patients possessed P482L(heterozygote) in south Korean\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e, while no P482L was identified in Chinese\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. The P482L variant is located at the carboxyl terminus (C-terminus) end of b\u003csup\u003e0,+\u003c/sup\u003eAT, which causes severe transporter defect comparative to those of frameshift and stop codon variant\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. Our previous study identified the \"VPP\" motif at the carboxyl terminus of b\u003csup\u003e0,+\u003c/sup\u003eAT regulate the ER-Golgi trafficking and thus control glycosylation of rBAT protein\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. The last P in the \"VPP\" motif represented the location of P482L variant. Since the location of P482L variant is the almost end of the C-terminus, we are speculating protein-protein interaction may be responsible for this functional defect, similar to the PDZ domain of URAT1\u003csup\u003e21\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eRelated to the genotype classification, the distribution of Type BB was found in 76%, while Type AA was only found in 12% of patients in the current Japanese study. In the UK study, Type AA is dominant (36%), followed by Type BB (26%). In the Chinese Study, 37.5% (3 out of 8) were Type AA, and 25% (2 out of 8) were Type BB. In a Korean study, 50% (4 out of 8) of patients were Type AA, and only one patient (12.5%) was type BB. These data indicated the global trends of \u003cem\u003eSLC3A1\u003c/em\u003e variant in European and even Asian Cystinuria patients. Thus, the predominance of Type BB genotype found in Japanese Cystinuria patients seems to be unique characteristics. Beside \u003cem\u003eSLC3A1\u003c/em\u003e and \u003cem\u003eSLC7A9\u003c/em\u003e, novel cystine transporter, AGT1 was identified\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. However, so far, no pathogenic variants were reported\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn a UK study, patients who have a variant in \u003cem\u003eSLC3A1\u003c/em\u003e(Type A or AA) demonstrated a significantly lower level of lysine, arginine, and ornithine, but not cystine compare to those of other patients\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. Another study from the UK presented no difference in the clinical parameter between Type AA and Type BB. Furthermore, patients with a single mutated allele demonstrated similar disease severity compare to those of 2 mutated alleles\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. In the current study, no difference in the severity of Cystinuria, such as urine cystine and age of onset, were observed based on the gene of variant (between \u003cem\u003eSLC3A1\u003c/em\u003e and \u003cem\u003eSLC7A9\u003c/em\u003e), genotype (between type AA and type BB), and the number of mutated alleles(between single and two variant alleles). The difference in the clinical phenotype may be derived from a wide difference in the basal genome variants, in which we found 14 novel variants (total of 28 variants) in \u003cem\u003eSLC3A1\u003c/em\u003e and \u003cem\u003eSLC7A9\u003c/em\u003e, respectively.\u003c/p\u003e \u003cp\u003eRecent evidence indicates the variant in the exon-intron boundary sequence resulted in the splicing error of the mRNA \u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e. About 9% of all variants reported in the Human Gene Mutation Database (HGMD) are splicing variants\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e. In general, variants in canonical acceptor and donor sites affect the strongly conserved sequences that define exon-intron boundaries. The most typical variants affect\u0026thinsp;+\u0026thinsp;1 and +\u0026thinsp;2 residues in the 5\u0026prime; splice site and \u0026minus;\u0026thinsp;1 and \u0026minus;\u0026thinsp;2 residues in the 3\u0026prime; acceptor splice site\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e. In the case of Neurofibromatosis type 1, c.1845\u0026thinsp;+\u0026thinsp;1G\u0026thinsp;\u0026gt;\u0026thinsp;A resulted in exon 15 and 16 skipping\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e. In the case of the c.1525-1G\u0026thinsp;\u0026gt;\u0026thinsp;A mutant variant in intron 9 of the CFTR gene resulted in the presence of three different mRNA isoforms\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e. Actually, it has been a missing piece of Cystinuria that up to 30% of patients did not fit into autosomal recessive inheritance category by exon variants\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e, which may be partially explained by variants in intron. In the current study, six exon-intron variants were identified, which resulted in the reclassification of the genotype. Among them, two patients previously identified no variant. One had homozygote, and the other had heterozygote exon-intron boundary variant. In the case with homozygote c.1224\u0026thinsp;+\u0026thinsp;3A\u0026thinsp;\u0026gt;\u0026thinsp;C variant in \u003cem\u003eSLC7A9\u003c/em\u003e, we have studied the mRNA expression of the \u003cem\u003eSLC3A1\u003c/em\u003e and \u003cem\u003eSLC7A9\u003c/em\u003e. Almost complete loss of \u003cem\u003eSLC7A9\u003c/em\u003e expression was observed by the exon-intron boundary variant. This data is, we believe, the first direct evidence of the significance of exon-intron boundary variant, which resulted in the loss of the transporter expression. Based on the genotype cover exon and exon-intron boundary, the cases that do not fit into the autosomal recessive inheritance category reduced to 9 cases from 14 cases. Based on the data, we propose genome classification based on the exon and exon-intron boundary.\u003c/p\u003e \u003cp\u003eWhen looking at the origin of Cystinuria patients among the Japanese population, most of the patients were found from the middle (Kanto and Tokai) and west (Kansai) side of Japan. No patient was found on the northeast side of Japan (Tohoku Area) except one patient in Hokkaido (Northern Island). The current Japanese population is proposed to be the result of admixture between the early migrants (Jomon people) and later migrants (Yayoi people). Jomon people lived in the Northern and Southern parts of Japan, while Yayoi people lived in the central part of Japan. Few Cystinuria patients from the northeast side of Japan may indicate Japanese Cystinuria patients' roots may be derived from Yayoi people, rather than Jomon people\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e. We are currently studying the association of Japanese Cystinuria patients with Yayoi or Jomon people based on the genome-wide SNP data, especially related to the P482L variant in \u003cem\u003eSLC7A9\u003c/em\u003e. Further analysis will lead to the link between P482L variant and origin of Japanese people.\u003c/p\u003e \u003cp\u003eThe current manuscript contained several limitations. First, the data was obtained from Chiba university hospital with the collaboration with the hospitals from 15 different prefectures ranged from the northern part (Hokkaido) and the west side (Kyusyu) of Japan. Although data is obtained from a wide range of locations, our data missed some of the location in Japan. Second, the data is obtained in a retrospective manner. In order to improve the quality of the data, we are currently organizing the prospective registry system for kidney stone patients (CRYSTAL-J), including the patients with Cystinuria. Third, presence of splicing error induced by the exon-intron boundary variants has not fully been validated except one case presented. We are currently assessing the presence of splicing error due to the variants in exon-intron boundaries by in vitro transcription. Fourth, based on the previous evidence, about 25% of Cystinuria patients develop non-cystine stone\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e. It will be next project to assess the risk factors for the development of non-cystine stone among Japanese Cystinuria cohort.\u003c/p\u003e \u003cp\u003eIn conclusion, the current manuscript described the genomic and clinical signature of Japanese Cystinuria patients, which is distinct from not only European Cystinuria patients but also from Asian Cystinuria patients. Genotype classification may be updated based on not only exon but also exon-intron boundary variants.\u003c/p\u003e "},{"header":"Methods","content":"\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003cdiv id=\"Sec13\" class=\"Section3\"\u003e \u003ch2\u003ePatient information\u003c/h2\u003e \u003cp\u003ePatients recruited to this study all had a clinical diagnosis of Cystinuria on the basis of clinical diagnosis of cystine stones from the southwest to northeast part of Japan between 2000 and 2020. Detailed clinical data were retrospectively collected. Demographics (age, sex and ethnicity) and age at the first stone events, treatment history, and urine biochemistry were collected.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eDefinition of urine amino acids\u003c/h2\u003e \u003cp\u003eCystine, lysine, arginine, and ornithine were measured by twenty-four hours urine sample. The amount of urine amino acids was determined by high performance liquid chromatography (HPLC) at SRL, Inc. (Hachioji, Tokyo, Japan).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eMann-Whitney's U test, ANOVA analysis, and the χ2 test were used for comparisons of two or three groups. Spearman's rank correlation coefficient was used to analyze the relationship between the two groups. Statistical computations were performed using JMP 11.0.0 (SAS Institute, NC, USA). P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered significant.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eGenetic Analysis\u003c/h2\u003e \u003cp\u003eGenomic DNA was extracted from whole blood using the Blood \u0026amp; Cell Culture DNA Midi Kit (Qiagen, Hilden, Germany). Genetic variants of SLC3A1 (NM_000341.3) and SLC7A9 (NM_001126335.1) were analyzed by next-generation sequence of the protein-coding exons and their intron boundaries essentially as described previously\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e. In brief, libraries for the next generation sequence were made by a KAPA Hyper Plus Library Kit. Hybridization capture was made by predesigned hybridization capture probes for SLC3A1 and SLC7A9 purchased from IDT. The libraries were sequenced on an Illumina NextSeq500. Variant calling was done using GATKv4 (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://gatk.broadinstitute.org/hc/en-us\u003c/span\u003e\u003cspan address=\"https://gatk.broadinstitute.org/hc/en-us\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). The variants thus detected by the next-generation sequencing were again confirmed by Sanger sequencing. The next-generation sequencing analysis was conducted at the Kazusa DNA Research Institute (Kisarazu, Chiba, Japan). Unreported (novel) variant was defined as the variant not reported on the previous publication. These gene variants are described with reference to the sequence of NM_000341.3\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eRNA sequencing\u003c/h2\u003e \u003cp\u003eThe kidney tissue was obtained by biopsy. Total RNA from kidney biopsy sample was extracted using the RNeasy Mini Kit (Qiagen, Hilden, Germany). RNA sequencing libraries were prepared using a SureSelect Strand-Specific RNA Library Prep Kit (Agilent Technologies, Inc., Santa Clara, CA, USA). Sequencing was performed on a HiSeq 2500 system (Illumina, Santiago, CA, USA) in a 50-base single-end mode. TopHat (version 2.1.0; with default parameters) was used to map to the human reference genome (hg38). Then, gene expression levels were quantified using Cufflinks version 2.2.1; with default parameters) and are expressed as the number of fragments per kilobase of exon per million reads mapped (FPKM).\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eEthical Approval and Consent to Participate\u003c/strong\u003e \u003cp\u003e The present study was conducted in accordance with ethical standards that promote and ensure respect and integrity for all human subjects and the Declaration of Helsinki. This study was approved by the institutional review board of Chiba University Hospital (approval number 1050), Nagoya City University Hospital (approval number of 70-19-0018) and other participated hospitals and written informed consent was obtained from all patients.\u003c/p\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eConflict of interest\u003c/h2\u003e \u003cp\u003eThe authors declare no competing financial interests.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding information\u003c/h2\u003e \u003cp\u003eThe present work was supported by 5th research grant from Japanese Society on Urolithiasis Research to S. Sakamoto, the Japan Agency for Medical Research and Development, the Initiative on Rare and Undiagnosed Diseases (IRUD) to T. Ichikawa and the Japan Agency for Medical Research and Development (AMED) (JP21ek0109549)to T. Ichikawa.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eYN and SS conceived and designed the experiments. JR, MM, SS, ST, NS, CI and YI analyzed the data. AA, AC, KW, MN, MF, YS, TU, TY, YK, YN, YY, KA, YI, MS, NA and TI supervised the study. AT, SH and KT provided the samples.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eThe authors thank Osamu Ohara (Kazusa DNA Research Institute, Kisarazu, Japan) for the NGS analysis and RNA sequence. The authors also thank Chiaki Hosaka for organizing the data. The author also thanks, Natsuko Kusama, Masako Takahashi, Hisayo Karahi, Keiko Yamazaki (Experimental assistant, Chiba University) for their support of this study.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe data was generated based on the funding from the Japanese Society on Urolithiasis Research (JSUR), the Initiative on Rare and Undiagnosed Diseases (IRUD) and the Japan Agency for Medical Research and Development (AMED). The data are available from the authors upon reasonable request and with the permission of the JSUR. The contact should be made to a corresponding author: Shinichi Sakamoto, E-mail: [email protected], Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuou-ku, Chiba, Japan.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eShigeta, Y. et al. 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Heterogeneous mutations in the SLC3A1 and SLC7A9 genes in Chinese patients with cystinuria. \u003cem\u003eKidney Int.\u003c/em\u003e \u003cb\u003e69\u003c/b\u003e, 123\u0026ndash;128. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/sj.ki.5000003\u003c/span\u003e\u003cspan address=\"10.1038/sj.ki.5000003\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2006).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSakamoto, S. et al. Chronological changes in epidemiological characteristics of lower urinary tract urolithiasis in Japan. \u003cem\u003eInt. J. 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Splicing mutations in human genetic disorders: examples, detection, and confirmation (vol 59, pg 253, 2018). \u003cem\u003eJ Appl Genet\u003c/em\u003e 60, 231\u0026ndash;231, doi: (2019). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s13353-019-00493-z\u003c/span\u003e\u003cspan address=\"10.1007/s13353-019-00493-z\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFang, L. J. et al. A novel mutation in the neurofibromatosis type 1 (NF1) gene promotes skipping of two exons by preventing exon definition. \u003cem\u003eJ. Mol. Biol.\u003c/em\u003e \u003cb\u003e307\u003c/b\u003e, 1261\u0026ndash;1270. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1006/jmbi.2001.4561\u003c/span\u003e\u003cspan address=\"10.1006/jmbi.2001.4561\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2001).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRamalho, A. S. et al. Transcript analysis of the cystic fibrosis splicing mutation 1525-1G\u0026thinsp;\u0026gt;\u0026thinsp;A shows use of multiple alternative splicing sites and suggests a putative role of exonic splicing enhancers. \u003cem\u003eJ. Med. 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Diagn.\u003c/em\u003e \u003cb\u003e20\u003c/b\u003e, 572\u0026ndash;582. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.jmoldx.2018.04.004\u003c/span\u003e\u003cspan address=\"10.1016/j.jmoldx.2018.04.004\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2018).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"545\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"2\"\u003e\n \u003cp\u003eTable 1. Demographic and clinical data\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"62.08791208791209%\"\u003e\n \u003cp\u003eCharacteristic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"37.91208791208791%\"\u003e\n \u003cp\u003evalue\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"62.08791208791209%\"\u003e\n \u003cp\u003enumber of patients (N)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"37.91208791208791%\"\u003e\n \u003cp\u003e101\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"62.08791208791209%\"\u003e\n \u003cp\u003eMedian age at presentation (years) (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"37.91208791208791%\"\u003e\n \u003cp\u003e17.0 (0-58)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"62.08791208791209%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Less than 10 years/teen age/20s/30s and over\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"37.91208791208791%\"\u003e\n \u003cp\u003e38/24/25/13(%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"62.08791208791209%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Male\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"37.91208791208791%\"\u003e\n \u003cp\u003e17.0 (0-48)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"62.08791208791209%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Female\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"37.91208791208791%\"\u003e\n \u003cp\u003e16.5 (0-58)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"62.08791208791209%\"\u003e\n \u003cp\u003eSex: male (N=65)/ female (N=36)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"37.91208791208791%\"\u003e\n \u003cp\u003e64.4%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"62.08791208791209%\"\u003e\n \u003cp\u003eFamily Histroy \u0026nbsp;(1st sibling/2nd sibling)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"37.91208791208791%\"\u003e\n \u003cp\u003e29% (19%/10%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"62.08791208791209%\"\u003e\n \u003cp\u003eEthnicity: Japanese\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"37.91208791208791%\"\u003e\n \u003cp\u003e100%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"62.08791208791209%\"\u003e\n \u003cp\u003eMedian age at follow-up (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"37.91208791208791%\"\u003e\n \u003cp\u003e33.0 (0.3-78.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"62.08791208791209%\"\u003e\n \u003cp\u003eMedian time from initial symptoms to follow-up (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"37.91208791208791%\"\u003e\n \u003cp\u003e14.0 (0.0-56.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"62.08791208791209%\"\u003e\n \u003cp\u003e\u0026nbsp;Cystine (\u0026mu;mol/day)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"37.91208791208791%\"\u003e\n \u003cp\u003e1745.7 (184.6 - 5303.4 )\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"62.08791208791209%\"\u003e\n \u003cp\u003e\u0026nbsp;Ornithine (\u0026mu;mol/day)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"37.91208791208791%\"\u003e\n \u003cp\u003e2044.3 (205.2 - 7471.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"62.08791208791209%\"\u003e\n \u003cp\u003e\u0026nbsp;Lysine (\u0026mu;mol/day)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"37.91208791208791%\"\u003e\n \u003cp\u003e8646.7 (536.9 - 36961.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"62.08791208791209%\"\u003e\n \u003cp\u003e\u0026nbsp;Arginine (\u0026mu;mol/day)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"37.91208791208791%\"\u003e\n \u003cp\u003e3334.2 (96.3 - 12096.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"597\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"8\"\u003e\n \u003cp\u003eTable 2. List of variants in \u003cem\u003eSLC3A1\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003e\u003cstrong\u003eSLC3A1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariant Type\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.302013422818792%\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariants\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;Protein Sequence\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.738255033557047%\"\u003e\n \u003cp\u003e\u003cstrong\u003eHomo/Hetero\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003e\u003cstrong\u003ePT Number\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.59731543624161%\"\u003e\n \u003cp\u003e\u003cstrong\u003eExon\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.436241610738255%\"\u003e\n \u003cp\u003e\u003cstrong\u003eLocation\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003eMissense\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.302013422818792%\"\u003e\n \u003cp\u003ec.283G\u0026gt;A*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003ep.Ala95Thr\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.738255033557047%\"\u003e\n \u003cp\u003eHetero\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.59731543624161%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.436241610738255%\"\u003e\n \u003cp\u003eTM1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003eMissense\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.302013422818792%\"\u003e\n \u003cp\u003ec.313A\u0026gt;G*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003ep.Ile105Val\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.738255033557047%\"\u003e\n \u003cp\u003eHetero\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.59731543624161%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.436241610738255%\"\u003e\n \u003cp\u003eTM1\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003eMissense\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.302013422818792%\"\u003e\n \u003cp\u003ec.470T\u0026gt;C*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003ep.Ile157Thr\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.738255033557047%\"\u003e\n \u003cp\u003eHetero\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.59731543624161%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.436241610738255%\"\u003e\n \u003cp\u003eExtra\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003eMissense\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.302013422818792%\"\u003e\n \u003cp\u003ec.548T\u0026gt;C*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003ep.Val183Ala\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.738255033557047%\"\u003e\n \u003cp\u003eHetero\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.59731543624161%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.436241610738255%\"\u003e\n \u003cp\u003eExtra\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003eMissense\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.302013422818792%\"\u003e\n \u003cp\u003ec.659A\u0026gt;G*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003ep.His220Arg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.738255033557047%\"\u003e\n \u003cp\u003eHetero\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.59731543624161%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.436241610738255%\"\u003e\n \u003cp\u003eExtra\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003eMissense\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.302013422818792%\"\u003e\n \u003cp\u003ec.763T\u0026gt;A *\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003ep.Trp255Arg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.738255033557047%\"\u003e\n \u003cp\u003eHetero\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.59731543624161%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.436241610738255%\"\u003e\n \u003cp\u003eExtra\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003eMissense\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.302013422818792%\"\u003e\n \u003cp\u003ec.989A\u0026gt;C*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003ep.Gln330Pro\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.738255033557047%\"\u003e\n \u003cp\u003eHetero\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.59731543624161%\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.436241610738255%\"\u003e\n \u003cp\u003eExtra\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003eMissense\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.302013422818792%\"\u003e\n \u003cp\u003ec.1037T\u0026gt;C\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003ep.Leu346Pro\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.738255033557047%\"\u003e\n \u003cp\u003eHetero\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.59731543624161%\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.436241610738255%\"\u003e\n \u003cp\u003eExtra\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003eMissense\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.302013422818792%\"\u003e\n \u003cp\u003ec.1323C\u0026gt;G*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003ep.Pro441Arg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.738255033557047%\"\u003e\n \u003cp\u003eHetero\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.59731543624161%\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.436241610738255%\"\u003e\n \u003cp\u003eExtra\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003eMissense\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.302013422818792%\"\u003e\n \u003cp\u003ec.1334T\u0026gt;C\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003ep.Ile445Thr\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.738255033557047%\"\u003e\n \u003cp\u003eHetero\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.59731543624161%\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.436241610738255%\"\u003e\n \u003cp\u003eExtra\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003eMissense\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.302013422818792%\"\u003e\n \u003cp\u003ec.1742T\u0026gt;G*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003ep.Val581Gly\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.738255033557047%\"\u003e\n \u003cp\u003eHetero\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.59731543624161%\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.436241610738255%\"\u003e\n \u003cp\u003eExtra\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003eMissense\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.302013422818792%\"\u003e\n \u003cp\u003ec.1772G\u0026gt;A *\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003ep.Arg591Lys\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.738255033557047%\"\u003e\n \u003cp\u003eHetero\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.59731543624161%\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.436241610738255%\"\u003e\n \u003cp\u003eExtra\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003eMissense\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.302013422818792%\"\u003e\n \u003cp\u003ec.2017T\u0026gt;C\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003ep.Cys673Arg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.738255033557047%\"\u003e\n \u003cp\u003eHetero\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.59731543624161%\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.436241610738255%\"\u003e\n \u003cp\u003eExtra\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003eNonsense\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.302013422818792%\"\u003e\n \u003cp\u003ec.1113C\u0026gt;A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003ep.Tyr371X\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.738255033557047%\"\u003e\n \u003cp\u003eHetero\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.59731543624161%\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.436241610738255%\"\u003e\n \u003cp\u003eExtra\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003eNonsense\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.302013422818792%\"\u003e\n \u003cp\u003ec.1328G\u0026gt;A*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003ep.Trp443X\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.738255033557047%\"\u003e\n \u003cp\u003eHomo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.59731543624161%\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.436241610738255%\"\u003e\n \u003cp\u003eExtra\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003eFrameshift\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.302013422818792%\"\u003e\n \u003cp\u003ec.1323dupT*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003ep.Asn442fs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.738255033557047%\"\u003e\n \u003cp\u003eHetero\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.59731543624161%\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.436241610738255%\"\u003e\n \u003cp\u003eExtra\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003eFrameshift\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.302013422818792%\"\u003e\n \u003cp\u003ec.1820delT\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003ep.Leu607fs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.738255033557047%\"\u003e\n \u003cp\u003eHetero\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.59731543624161%\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.436241610738255%\"\u003e\n \u003cp\u003eExtra\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003eFrameshift\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.302013422818792%\"\u003e\n \u003cp\u003ec.1820delT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003ep.Leu607fs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.738255033557047%\"\u003e\n \u003cp\u003eHomo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.59731543624161%\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.436241610738255%\"\u003e\n \u003cp\u003eExtra\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003eFrameshift\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.302013422818792%\"\u003e\n \u003cp\u003ec.1898_1899insAT*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003ep.Asp634fs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.738255033557047%\"\u003e\n \u003cp\u003eHomo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.59731543624161%\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.436241610738255%\"\u003e\n \u003cp\u003eExtra\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003eSplice site\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.302013422818792%\"\u003e\n \u003cp\u003ec.1500+1G\u0026gt;A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"10.738255033557047%\"\u003e\n \u003cp\u003eHetero\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.59731543624161%\"\u003e\n \u003cp\u003e8+1 intro\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.436241610738255%\"\u003e\n \u003cp\u003eExtra\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003eSplice site\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.302013422818792%\"\u003e\n \u003cp\u003ec.1617+1_1617+2dupGT*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.738255033557047%\"\u003e\n \u003cp\u003eHetero\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.59731543624161%\"\u003e\n \u003cp\u003e9+1+2 intron\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.436241610738255%\"\u003e\n \u003cp\u003eExtra\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003eDeletions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.302013422818792%\"\u003e\n \u003cp\u003eEx10 deletion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"10.738255033557047%\"\u003e\n \u003cp\u003eHomo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.731543624161073%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.59731543624161%\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.436241610738255%\"\u003e\n \u003cp\u003eExtra\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"8\"\u003e\n \u003cp\u003eMissense: missense variant, Frameshift: frame shift variant, Nonsense: nonsense variant, Frameshift: frameshift variant, Splice site: splice site variant (exon-intron boundary variant), TM: transmembrane domain, Extra: extracellular domain, new: novel variant not reported previously. These gene variants are described with reference to the sequence of NM_000341.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"603\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"8\"\u003e\n \u003cp\u003eTable 3. List of variants in\u003cem\u003e\u0026nbsp;SLC7A9\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.623548922056385%\"\u003e\n \u003cp\u003e\u003cstrong\u003eSLC7A9\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.613598673300165%\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariant Type\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.563847429519072%\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariants\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.276948590381426%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;Protein Sequence\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.106135986733001%\"\u003e\n \u003cp\u003e\u003cstrong\u003eHomo/Hetero\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.286898839137645%\"\u003e\n \u003cp\u003e\u003cstrong\u003ePT Number\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.930348258706468%\"\u003e\n \u003cp\u003e\u003cstrong\u003eExon\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.598673300165837%\"\u003e\n \u003cp\u003e\u003cstrong\u003eLocation\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.623548922056385%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.613598673300165%\"\u003e\n \u003cp\u003eMissense\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.563847429519072%\"\u003e\n \u003cp\u003ec.2T\u0026gt;C \u0026nbsp; new\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.276948590381426%\"\u003e\n \u003cp\u003ep.Met1Thr\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.106135986733001%\"\u003e\n \u003cp\u003eHetero\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.286898839137645%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.930348258706468%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.598673300165837%\"\u003e\n \u003cp\u003eCytoplasmic\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.623548922056385%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.613598673300165%\"\u003e\n \u003cp\u003eMissense\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.563847429519072%\"\u003e\n \u003cp\u003ec.206G\u0026gt;A\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.276948590381426%\"\u003e\n \u003cp\u003ep.Trp69X\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.106135986733001%\"\u003e\n \u003cp\u003eHetero\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.286898839137645%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.930348258706468%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.598673300165837%\"\u003e\n \u003cp\u003eTM2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.623548922056385%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.613598673300165%\"\u003e\n \u003cp\u003eMissense\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.563847429519072%\"\u003e\n \u003cp\u003ec.209C\u0026gt;T\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.276948590381426%\"\u003e\n \u003cp\u003ep.Ala70Val\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.106135986733001%\"\u003e\n \u003cp\u003eHetero\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.286898839137645%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.930348258706468%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.598673300165837%\"\u003e\n \u003cp\u003eTM2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.623548922056385%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.613598673300165%\"\u003e\n \u003cp\u003eMissense\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.563847429519072%\"\u003e\n \u003cp\u003ec.217G\u0026gt;A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.276948590381426%\"\u003e\n \u003cp\u003ep.Gly73Arg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.106135986733001%\"\u003e\n \u003cp\u003eHetero\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.286898839137645%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.930348258706468%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.598673300165837%\"\u003e\n \u003cp\u003eTM2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.623548922056385%\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.613598673300165%\"\u003e\n \u003cp\u003eMissense\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.563847429519072%\"\u003e\n \u003cp\u003ec.308C\u0026gt;T \u0026nbsp; new\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.276948590381426%\"\u003e\n \u003cp\u003ep.Ala103Val\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.106135986733001%\"\u003e\n \u003cp\u003eHetero\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.286898839137645%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.930348258706468%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.598673300165837%\"\u003e\n \u003cp\u003eTM3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.623548922056385%\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.613598673300165%\"\u003e\n \u003cp\u003eMissense\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.563847429519072%\"\u003e\n \u003cp\u003ec.511C\u0026gt;T\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.276948590381426%\"\u003e\n \u003cp\u003ep.Arg171Trp\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.106135986733001%\"\u003e\n \u003cp\u003eHetero\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.286898839137645%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.930348258706468%\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.598673300165837%\"\u003e\n \u003cp\u003eCytoplasmic Loop2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.623548922056385%\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.613598673300165%\"\u003e\n \u003cp\u003eMissense\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.563847429519072%\"\u003e\n \u003cp\u003ec.583G\u0026gt;A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.276948590381426%\"\u003e\n \u003cp\u003ep.Gly195Arg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.106135986733001%\"\u003e\n \u003cp\u003eHetero\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.286898839137645%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.930348258706468%\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.598673300165837%\"\u003e\n \u003cp\u003eTM5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.623548922056385%\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.613598673300165%\"\u003e\n \u003cp\u003eMissense\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.563847429519072%\"\u003e\n \u003cp\u003ec.650C\u0026gt;G \u0026nbsp; new\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.276948590381426%\"\u003e\n \u003cp\u003ep.Ser217Cys\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.106135986733001%\"\u003e\n \u003cp\u003eHetero\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.286898839137645%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.930348258706468%\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.598673300165837%\"\u003e\n \u003cp\u003eTM6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.623548922056385%\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.613598673300165%\"\u003e\n \u003cp\u003eMissense\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.563847429519072%\"\u003e\n \u003cp\u003ec.671C\u0026gt;T\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.276948590381426%\"\u003e\n \u003cp\u003ep.Ala224Val\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.106135986733001%\"\u003e\n \u003cp\u003eHetero\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.286898839137645%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.930348258706468%\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.598673300165837%\"\u003e\n \u003cp\u003eTM6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.623548922056385%\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.613598673300165%\"\u003e\n \u003cp\u003eMissense\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.563847429519072%\"\u003e\n \u003cp\u003ec.679A\u0026gt;G\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.276948590381426%\"\u003e\n \u003cp\u003ep.Asn227Asp\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.106135986733001%\"\u003e\n \u003cp\u003eHetero\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.286898839137645%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.930348258706468%\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.598673300165837%\"\u003e\n \u003cp\u003eTM6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.623548922056385%\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.613598673300165%\"\u003e\n \u003cp\u003eMissense\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.563847429519072%\"\u003e\n \u003cp\u003ec.698A\u0026gt;G \u0026nbsp; new\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.276948590381426%\"\u003e\n \u003cp\u003ep.Asp233Gly\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.106135986733001%\"\u003e\n \u003cp\u003eHomo/Hetero\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.286898839137645%\"\u003e\n \u003cp\u003e1/1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.930348258706468%\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.598673300165837%\"\u003e\n \u003cp\u003eCytoplasmic Loop3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.623548922056385%\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.613598673300165%\"\u003e\n \u003cp\u003eMissense\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.563847429519072%\"\u003e\n \u003cp\u003ec.829G\u0026gt;A \u0026nbsp; new\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.276948590381426%\"\u003e\n \u003cp\u003ep.Val277Met\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.106135986733001%\"\u003e\n \u003cp\u003eHetero\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.286898839137645%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.930348258706468%\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.598673300165837%\"\u003e\n \u003cp\u003eExtra Loop4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.623548922056385%\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.613598673300165%\"\u003e\n \u003cp\u003eMissense\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.563847429519072%\"\u003e\n \u003cp\u003ec.886C\u0026gt;G \u0026nbsp; new\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.276948590381426%\"\u003e\n \u003cp\u003ep.Arg296Gly\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.106135986733001%\"\u003e\n \u003cp\u003eHetero\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.286898839137645%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.930348258706468%\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.598673300165837%\"\u003e\n \u003cp\u003eExtra Loop4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.623548922056385%\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.613598673300165%\"\u003e\n \u003cp\u003eMissense\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.563847429519072%\"\u003e\n \u003cp\u003ec.968C\u0026gt;T \u0026nbsp; new\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.276948590381426%\"\u003e\n \u003cp\u003ep.Thr323Ile\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.106135986733001%\"\u003e\n \u003cp\u003eHetero\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.286898839137645%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.930348258706468%\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.598673300165837%\"\u003e\n \u003cp\u003eCytoplasmic Loop4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.623548922056385%\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.613598673300165%\"\u003e\n \u003cp\u003eMissense\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.563847429519072%\"\u003e\n \u003cp\u003ec.974G\u0026gt;T \u0026nbsp; new\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.276948590381426%\"\u003e\n \u003cp\u003ep.Gly325Val\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.106135986733001%\"\u003e\n \u003cp\u003eHetero\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.286898839137645%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.930348258706468%\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.598673300165837%\"\u003e\n \u003cp\u003eCytoplasmic Loop4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.623548922056385%\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.613598673300165%\"\u003e\n \u003cp\u003eMissense\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.563847429519072%\"\u003e\n \u003cp\u003ec.992C\u0026gt;T\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.276948590381426%\"\u003e\n \u003cp\u003ep.Ala331Val\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.106135986733001%\"\u003e\n \u003cp\u003eHomo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.286898839137645%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.930348258706468%\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.598673300165837%\"\u003e\n \u003cp\u003eCytoplasmic Loop4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.623548922056385%\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.613598673300165%\"\u003e\n \u003cp\u003eMissense\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.563847429519072%\"\u003e\n \u003cp\u003ec.998G\u0026gt;A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.276948590381426%\"\u003e\n \u003cp\u003ep.Arg333Gln\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.106135986733001%\"\u003e\n \u003cp\u003eHetero\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.286898839137645%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.930348258706468%\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.598673300165837%\"\u003e\n \u003cp\u003eCytoplasmic Loop4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.623548922056385%\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.613598673300165%\"\u003e\n \u003cp\u003eMissense\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.563847429519072%\"\u003e\n \u003cp\u003ec.1061C\u0026gt;A\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.276948590381426%\"\u003e\n \u003cp\u003ep.Ala354Asp\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.106135986733001%\"\u003e\n \u003cp\u003eHetero\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.286898839137645%\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.930348258706468%\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.598673300165837%\"\u003e\n \u003cp\u003eTM9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.623548922056385%\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.613598673300165%\"\u003e\n \u003cp\u003eMissense\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.563847429519072%\"\u003e\n \u003cp\u003ec.1124T\u0026gt;C \u0026nbsp; new\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.276948590381426%\"\u003e\n \u003cp\u003ep.Val375Ala\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.106135986733001%\"\u003e\n \u003cp\u003eHomo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.286898839137645%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.930348258706468%\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.598673300165837%\"\u003e\n \u003cp\u003eTM10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.623548922056385%\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.613598673300165%\"\u003e\n \u003cp\u003eMissense\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.563847429519072%\"\u003e\n \u003cp\u003ec.1166C\u0026gt;T\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.276948590381426%\"\u003e\n \u003cp\u003ep.Thr389Met\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.106135986733001%\"\u003e\n \u003cp\u003eHetero\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.286898839137645%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.930348258706468%\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.598673300165837%\"\u003e\n \u003cp\u003eTM10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.623548922056385%\"\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.613598673300165%\"\u003e\n \u003cp\u003eMissense\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.563847429519072%\"\u003e\n \u003cp\u003ec.1336A\u0026gt;C \u0026nbsp; new\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.276948590381426%\"\u003e\n \u003cp\u003ep.Ser446Arg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.106135986733001%\"\u003e\n \u003cp\u003eHetero\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.286898839137645%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.930348258706468%\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.598673300165837%\"\u003e\n \u003cp\u003eTM12\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.623548922056385%\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.613598673300165%\"\u003e\n \u003cp\u003eMissense\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.563847429519072%\"\u003e\n \u003cp\u003ec.1445C\u0026gt;T\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.276948590381426%\"\u003e\n \u003cp\u003ep.pro482Leu\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.106135986733001%\"\u003e\n \u003cp\u003eHomo/Hetero\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.286898839137645%\"\u003e\n \u003cp\u003e43/30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.930348258706468%\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.598673300165837%\"\u003e\n \u003cp\u003eCytoplasmic\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.623548922056385%\"\u003e\n \u003cp\u003e23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.613598673300165%\"\u003e\n \u003cp\u003eFrameshift\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.563847429519072%\"\u003e\n \u003cp\u003ec.611_612delCA \u0026nbsp; new\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.276948590381426%\"\u003e\n \u003cp\u003ep.thr204fs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.106135986733001%\"\u003e\n \u003cp\u003eHetero\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.286898839137645%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.930348258706468%\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.598673300165837%\"\u003e\n \u003cp\u003eExtra Loop3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.623548922056385%\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.613598673300165%\"\u003e\n \u003cp\u003eFrameshift\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.563847429519072%\"\u003e\n \u003cp\u003ec.1017delA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.276948590381426%\"\u003e\n \u003cp\u003ep.Val340fs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.106135986733001%\"\u003e\n \u003cp\u003eHomo/Hetero\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.286898839137645%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.930348258706468%\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.598673300165837%\"\u003e\n \u003cp\u003eCytoplasmic Loop4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.623548922056385%\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.613598673300165%\"\u003e\n \u003cp\u003eSplice site\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.563847429519072%\"\u003e\n \u003cp\u003ec.873+2dupT \u0026nbsp; new\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.276948590381426%\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.106135986733001%\"\u003e\n \u003cp\u003eHetero\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.286898839137645%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.930348258706468%\"\u003e\n \u003cp\u003eIntron(Exon 8+2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.598673300165837%\"\u003e\n \u003cp\u003eExtra Loop4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.623548922056385%\"\u003e\n \u003cp\u003e26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.613598673300165%\"\u003e\n \u003cp\u003eSplice site\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.563847429519072%\"\u003e\n \u003cp\u003ec.1074+1G\u0026gt;A \u0026nbsp; new\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.276948590381426%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"12.106135986733001%\"\u003e\n \u003cp\u003eHetero\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.286898839137645%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.930348258706468%\"\u003e\n \u003cp\u003eIntron(Exon 10+1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.598673300165837%\"\u003e\n \u003cp\u003eExtra Loop5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.623548922056385%\"\u003e\n \u003cp\u003e27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.613598673300165%\"\u003e\n \u003cp\u003eSplice site\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.563847429519072%\"\u003e\n \u003cp\u003ec.1224+3A\u0026gt;C \u0026nbsp; new\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.276948590381426%\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.106135986733001%\"\u003e\n \u003cp\u003eHomo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.286898839137645%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.930348258706468%\"\u003e\n \u003cp\u003eIntron(Exon 11+3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.598673300165837%\"\u003e\n \u003cp\u003eCytoplasmic Loop5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.623548922056385%\"\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.613598673300165%\"\u003e\n \u003cp\u003eSplice site\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.563847429519072%\"\u003e\n \u003cp\u003ec.1399+4_1399+7delAGTA\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.276948590381426%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"12.106135986733001%\"\u003e\n \u003cp\u003eHetero\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.286898839137645%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.930348258706468%\"\u003e\n \u003cp\u003eIntron(Exon 12+4-7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.598673300165837%\"\u003e\n \u003cp\u003eTM12\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"8\"\u003e\n \u003cp\u003eMissense: missense variant, Frameshift: frame shift variant, Nonsense: nonsense variant, \u0026nbsp;Frameshift: frameshift variant, Splice site: splice site variant (exon-intron boundary variant), TM: transmembrane domain, Extra: extracellular domain, new: novel variant not reported previously. These gene variants are described with reference to the sequence of NM_000341.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"624\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"99.84%\" colspan=\"9\"\u003e\n \u003cp\u003eTable 4. Aminoacid concentration based on Genes, Genotype and P482L variant\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0.16%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"99.84%\" colspan=\"9\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eUrine Aminoacids: : \u0026micro;mol/day\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0.16%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.2%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"11.04%\"\u003e\n \u003cp\u003e\u003cstrong\u003eCystine\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.4%\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.76%\"\u003e\n \u003cp\u003e\u003cstrong\u003eOrnithine\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.6%\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.8%\"\u003e\n \u003cp\u003e\u003cstrong\u003eLysine\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.68%\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.8%\"\u003e\n \u003cp\u003e\u003cstrong\u003eArginine\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.72%\" colspan=\"2\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.2%\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.04%\"\u003e\n \u003cp\u003eMedian\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.4%\"\u003e\n \u003cp\u003eRange\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.76%\"\u003e\n \u003cp\u003eMedian\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.6%\"\u003e\n \u003cp\u003eRange\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.8%\"\u003e\n \u003cp\u003eMedian\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.68%\"\u003e\n \u003cp\u003eRange\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.8%\"\u003e\n \u003cp\u003eMedian\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.72%\" colspan=\"2\"\u003e\n \u003cp\u003eRange\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"99.84%\" colspan=\"9\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eBased on Genes\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0.16%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.2%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eSLC3A1\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.04%\"\u003e\n \u003cp\u003e1357.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.4%\"\u003e\n \u003cp\u003e(186.9-3117.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.76%\"\u003e\n \u003cp\u003e1692.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.6%\"\u003e\n \u003cp\u003e(861.3-3848.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.8%\"\u003e\n \u003cp\u003e7051.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.68%\"\u003e\n \u003cp\u003e(5307.9-12456.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.8%\"\u003e\n \u003cp\u003e2682.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.72%\" colspan=\"2\"\u003e\n \u003cp\u003e(323.4-4590.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.2%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eSLC7A9\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.04%\"\u003e\n \u003cp\u003e1832.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.4%\"\u003e\n \u003cp\u003e(184.6-5303.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.76%\"\u003e\n \u003cp\u003e2020.15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.6%\"\u003e\n \u003cp\u003e(205.2-7471.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.8%\"\u003e\n \u003cp\u003e8787.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.68%\"\u003e\n \u003cp\u003e(536.9-36961.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.8%\"\u003e\n \u003cp\u003e3334.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.72%\" colspan=\"2\"\u003e\n \u003cp\u003e(96.3-12096)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.2%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eSLC3A1/SLC7A9\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.04%\"\u003e\n \u003cp\u003e1434\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.4%\"\u003e\n \u003cp\u003e(1037.3-3722.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.76%\"\u003e\n \u003cp\u003e3174.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.6%\"\u003e\n \u003cp\u003e(2302.1-4316.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.8%\"\u003e\n \u003cp\u003e8144\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.68%\"\u003e\n \u003cp\u003e(1300.2-13826.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.8%\"\u003e\n \u003cp\u003e3495.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.72%\" colspan=\"2\"\u003e\n \u003cp\u003e(2269-5996.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"99.84%\" colspan=\"9\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eBased on Genotype\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0.16%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.2%\"\u003e\n \u003cp\u003e\u003cstrong\u003eAA\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.04%\"\u003e\n \u003cp\u003e1230.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.4%\"\u003e\n \u003cp\u003e(186.9-3117.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.76%\"\u003e\n \u003cp\u003e1355.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.6%\"\u003e\n \u003cp\u003e(861.3-3848.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.8%\"\u003e\n \u003cp\u003e5631.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.68%\"\u003e\n \u003cp\u003e(5307.9-9223.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.8%\"\u003e\n \u003cp\u003e1002.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.72%\" colspan=\"2\"\u003e\n \u003cp\u003e(323.4-4590.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.2%\"\u003e\n \u003cp\u003e\u003cstrong\u003eBB\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.04%\"\u003e\n \u003cp\u003e1815.45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.4%\"\u003e\n \u003cp\u003e(184.6-5303.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.76%\"\u003e\n \u003cp\u003e2036.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.6%\"\u003e\n \u003cp\u003e(205.2-7417.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.8%\"\u003e\n \u003cp\u003e8858.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.68%\"\u003e\n \u003cp\u003e(536.9-36961.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.8%\"\u003e\n \u003cp\u003e3334.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.72%\" colspan=\"2\"\u003e\n \u003cp\u003e(150.4-12096)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.2%\"\u003e\n \u003cp\u003e\u003cstrong\u003eAAB/BBA\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.04%\"\u003e\n \u003cp\u003e1434\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.4%\"\u003e\n \u003cp\u003e(1037.3-3722.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.76%\"\u003e\n \u003cp\u003e3174.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.6%\"\u003e\n \u003cp\u003e(2302.1-4316.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.8%\"\u003e\n \u003cp\u003e8144\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.68%\"\u003e\n \u003cp\u003e(1300.2-13826.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.8%\"\u003e\n \u003cp\u003e3495.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.72%\" colspan=\"2\"\u003e\n \u003cp\u003e(2269-5996.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.2%\"\u003e\n \u003cp\u003e\u003cstrong\u003eA\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.04%\"\u003e\n \u003cp\u003e3034.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.4%\"\u003e\n \u003cp\u003e(3034.6-3034.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.76%\"\u003e\n \u003cp\u003e2029.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.6%\"\u003e\n \u003cp\u003e(2029.4-2029.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.8%\"\u003e\n \u003cp\u003e12456.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.68%\"\u003e\n \u003cp\u003e(12456.5-12456.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.8%\"\u003e\n \u003cp\u003e4425.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.72%\" colspan=\"2\"\u003e\n \u003cp\u003e(4425.4-4425.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.2%\"\u003e\n \u003cp\u003e\u003cstrong\u003eB\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.04%\"\u003e\n \u003cp\u003e1968.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.4%\"\u003e\n \u003cp\u003e(592.8-4094.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.76%\"\u003e\n \u003cp\u003e1616.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.6%\"\u003e\n \u003cp\u003e(278.3-2843)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.8%\"\u003e\n \u003cp\u003e8576.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.68%\"\u003e\n \u003cp\u003e(3038.4-10211.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.8%\"\u003e\n \u003cp\u003e555.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.72%\" colspan=\"2\"\u003e\n \u003cp\u003e(96.3-5037.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"99.84%\" colspan=\"9\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eBased on P482L\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0.16%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.2%\"\u003e\n \u003cp\u003e\u003cstrong\u003eP482L Homo\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.04%\"\u003e\n \u003cp\u003e1705.15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.4%\"\u003e\n \u003cp\u003e(184.6-4368)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.76%\"\u003e\n \u003cp\u003e2195.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.6%\"\u003e\n \u003cp\u003e(205.2-4316.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.8%\"\u003e\n \u003cp\u003e8858.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.68%\"\u003e\n \u003cp\u003e(536.9-17412)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.8%\"\u003e\n \u003cp\u003e3423.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.72%\" colspan=\"2\"\u003e\n \u003cp\u003e(150.4-6531)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.2%\"\u003e\n \u003cp\u003e\u003cstrong\u003eP482L compound hetero\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.04%\"\u003e\n \u003cp\u003e2359.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.4%\"\u003e\n \u003cp\u003e(851-5303.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.76%\"\u003e\n \u003cp\u003e2183.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.6%\"\u003e\n \u003cp\u003e(716-7471.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.8%\"\u003e\n \u003cp\u003e8970.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.68%\"\u003e\n \u003cp\u003e(2968.4-36961.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.8%\"\u003e\n \u003cp\u003e3875.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.72%\" colspan=\"2\"\u003e\n \u003cp\u003e(1416.6-12096)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.2%\"\u003e\n \u003cp\u003e\u003cstrong\u003eP482L single Hetero\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.04%\"\u003e\n \u003cp\u003e1280.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.4%\"\u003e\n \u003cp\u003e(592.8-1968.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.76%\"\u003e\n \u003cp\u003e1560.65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.6%\"\u003e\n \u003cp\u003e(278.3-2843)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.8%\"\u003e\n \u003cp\u003e5807.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.68%\"\u003e\n \u003cp\u003e(3038.4-8576.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.8%\"\u003e\n \u003cp\u003e2567\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.72%\" colspan=\"2\"\u003e\n \u003cp\u003e(96.3-5037.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.2%\"\u003e\n \u003cp\u003e\u003cstrong\u003eNone P482L\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.04%\"\u003e\n \u003cp\u003e1483.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.4%\"\u003e\n \u003cp\u003e(186.9-4094.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.76%\"\u003e\n \u003cp\u003e1822.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.6%\"\u003e\n \u003cp\u003e(845.4-5497.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.8%\"\u003e\n \u003cp\u003e8594.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.68%\"\u003e\n \u003cp\u003e(2411.5-16476.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.8%\"\u003e\n \u003cp\u003e1729.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.72%\" colspan=\"2\"\u003e\n \u003cp\u003e(323.4-9512.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"651\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"75.6923076923077%\" colspan=\"6\"\u003e\n \u003cp\u003eTable 5. List of cases with Exon-Intron boundary variants\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.3076923076923075%\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.615384615384615%\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.384615384615385%\" colspan=\"2\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"2.914110429447853%\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"39.41717791411043%\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eSLC3A1\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.4539877300613497%\"\u003e\n \u003cp\u003e\u003cstrong\u003e \u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.67484662576687%\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eSLC7A9\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.3006134969325154%\"\u003e\n \u003cp\u003e\u003cstrong\u003e \u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.085889570552148%\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eGenotype\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0.15337423312883436%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"2.9185867895545314%\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"39.47772657450077%\" colspan=\"2\"\u003e\n \u003cp\u003eVariants\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.457757296466974%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"30.721966205837173%\" colspan=\"2\"\u003e\n \u003cp\u003eVariants\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.304147465437788%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"8.602150537634408%\"\u003e\n \u003cp\u003eExon only\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.36405529953917%\"\u003e\n \u003cp\u003eExon/Exon-Intron boundary\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0.15360983102918588%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"2.9185867895545314%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.508448540706606%\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.96927803379416%\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.457757296466974%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"17.665130568356375%\"\u003e\n \u003cp\u003eT204fs c.611_612delCA (hetero)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.056835637480798%\"\u003e\n \u003cp\u003ec.873+2dupT (hetero)*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.304147465437788%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"8.602150537634408%\"\u003e\n \u003cp\u003eType B\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.36405529953917%\"\u003e\n \u003cp\u003eType BB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0.15360983102918588%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"2.9185867895545314%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.508448540706606%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"19.96927803379416%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"2.457757296466974%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"17.665130568356375%\"\u003e\n \u003cp\u003ec.1224+3A\u0026gt;C (homo)*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.056835637480798%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"2.304147465437788%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"8.602150537634408%\"\u003e\n \u003cp\u003eNo mutation\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.36405529953917%\"\u003e\n \u003cp\u003eType BB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0.15360983102918588%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"2.9185867895545314%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.508448540706606%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"19.96927803379416%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"2.457757296466974%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"30.721966205837173%\" colspan=\"2\"\u003e\n \u003cp\u003ec.1399+4_1399+7delAGTA (hetero)*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.304147465437788%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"8.602150537634408%\"\u003e\n \u003cp\u003eNo mutation\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.36405529953917%\"\u003e\n \u003cp\u003eType B\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0.15360983102918588%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"2.9185867895545314%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.508448540706606%\"\u003e\n \u003cp\u003eY371Ter(hetero)C1113A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.96927803379416%\"\u003e\n \u003cp\u003ec.1500+1G\u0026gt;A (hetero)*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.457757296466974%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"17.665130568356375%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"13.056835637480798%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"2.304147465437788%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"8.602150537634408%\"\u003e\n \u003cp\u003eType A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.36405529953917%\"\u003e\n \u003cp\u003eType AA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0.15360983102918588%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"2.9185867895545314%\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.508448540706606%\"\u003e\n \u003cp\u003eP441R(hetero)C1322G\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.96927803379416%\"\u003e\n \u003cp\u003ec.1617+1_1617+2dupGT (hetero)*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.457757296466974%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"17.665130568356375%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"13.056835637480798%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"2.304147465437788%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"8.602150537634408%\"\u003e\n \u003cp\u003eType A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.36405529953917%\"\u003e\n \u003cp\u003eType AA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0.15360983102918588%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"2.9185867895545314%\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.508448540706606%\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.96927803379416%\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.457757296466974%\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.665130568356375%\"\u003e\n \u003cp\u003eP482L(hetero)C1445T\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.056835637480798%\"\u003e\n \u003cp\u003ec.1074+1G\u0026gt;A (hetero)*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.304147465437788%\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.602150537634408%\"\u003e\n \u003cp\u003eType B\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.36405529953917%\"\u003e\n \u003cp\u003eType BB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0.15360983102918588%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"2.914110429447853%\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"96.93251533742331%\" colspan=\"8\"\u003e\n \u003cp\u003e* Exon-Intron boundary (Splice site) variant\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"0.15337423312883436%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"593\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"9\"\u003e\n \u003cp\u003eTable 6. Urine aminoacid concentration based on Exon/Exon-intron boundary variants\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.200674536256322%\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"82.79932546374367%\" colspan=\"8\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eUrine Aminoacids: : \u0026micro;mol/day\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.200674536256322%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"9.443507588532883%\"\u003e\n \u003cp\u003e\u003cstrong\u003eCystine\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.141652613827993%\"\u003e\n \u003cp\u003e\u003cstrong\u003e \u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.612141652613827%\"\u003e\n \u003cp\u003e\u003cstrong\u003eOrnithine\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.298482293423271%\"\u003e\n \u003cp\u003e\u003cstrong\u003e \u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.094435075885329%\"\u003e\n \u003cp\u003e\u003cstrong\u003eLysine\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.141652613827993%\"\u003e\n \u003cp\u003e\u003cstrong\u003e \u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.768971332209107%\"\u003e\n \u003cp\u003e\u003cstrong\u003eArginine\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.298482293423271%\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.200674536256322%\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.443507588532883%\"\u003e\n \u003cp\u003eMedian\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.141652613827993%\"\u003e\n \u003cp\u003eRange\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.612141652613827%\"\u003e\n \u003cp\u003eMedian\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.298482293423271%\"\u003e\n \u003cp\u003eRange\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.094435075885329%\"\u003e\n \u003cp\u003eMedian\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.141652613827993%\"\u003e\n \u003cp\u003eRange\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.768971332209107%\"\u003e\n \u003cp\u003eMedian\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.298482293423271%\"\u003e\n \u003cp\u003eRange\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.200674536256322%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eExon variant\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.443507588532883%\"\u003e\n \u003cp\u003e1705.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.141652613827993%\"\u003e\n \u003cp\u003e(184.6-5303.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.612141652613827%\"\u003e\n \u003cp\u003e2044.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.298482293423271%\"\u003e\n \u003cp\u003e(205.2-7471.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.094435075885329%\"\u003e\n \u003cp\u003e8538.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.141652613827993%\"\u003e\n \u003cp\u003e(536.9-36961.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.768971332209107%\"\u003e\n \u003cp\u003e3512.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.298482293423271%\"\u003e\n \u003cp\u003e(96.3-12096)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.200674536256322%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eExon-intron boundary variant\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.443507588532883%\"\u003e\n \u003cp\u003e3214.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.141652613827993%\"\u003e\n \u003cp\u003e(1025.6-4094.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.612141652613827%\"\u003e\n \u003cp\u003e2732.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.298482293423271%\"\u003e\n \u003cp\u003e(845.4-3922.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.094435075885329%\"\u003e\n \u003cp\u003e9134.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.141652613827993%\"\u003e\n \u003cp\u003e(2411.5-10211.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.768971332209107%\"\u003e\n \u003cp\u003e1169.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.298482293423271%\"\u003e\n \u003cp\u003e(555.9-4362.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Cystinuria, Urinary Stone, Genetic variant, Germline variant","lastPublishedDoi":"10.21203/rs.3.rs-4889642/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4889642/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eCystinuria is the most common genetic cause of urinary stones. Defect in \u003cem\u003eSLC3A1\u003c/em\u003e/\u003cem\u003eSLC7A9\u003c/em\u003e genes coding cystine transporter proteins rBAT/b\u003csup\u003e0,+\u003c/sup\u003eAT will cause Cystinuria. The current work analyzed the clinical and genetics characteristics of Japanese Cystinuria patients. In total, 101 Cystinuria patients were studied. Clinical phenotypes were defined, and genetic analysis of \u003cem\u003eSLC3A1\u003c/em\u003e and \u003cem\u003eSLC7A9 \u003c/em\u003eby next-generation sequence was performed. Excretion of urine cystine were determined by twenty-four hours urine analysis. The median age of presentation was 17 years old. In total, 51 different mutant variant alleles were identified (22 and 28 mutant variants in \u003cem\u003eSLC3A1\u003c/em\u003e and \u003cem\u003eSLC7A9\u003c/em\u003e, respectively), including 28 novel variants. The p.pro482Leu (c.1445C\u0026thinsp;\u0026gt;\u0026thinsp;T) variant in \u003cem\u003eSCL7A9\u003c/em\u003e was predominantly found in 73 patients. Variants in exon-intron boundaries were identified in 6 cases. The patient with homozygote intron (exon-intron boundary) variant in \u003cem\u003eSCL7A9\u003c/em\u003e presented a severe phenotype with significant loss of mRNA expression. Inclusion of exon and exon-intron boundary variants reduced the number of cases that did not fit autosomal recessive inheritance from 14\u0026ndash;9%. Predominance of p.pro482Leu (c.1445C\u0026thinsp;\u0026gt;\u0026thinsp;T) variant in SCL7A9 was a unique characteristic of Japanese Cystinuria. Current data may provide a rationale for the inclusion of exon-intron boundary variants in genomic classification.\u003c/p\u003e","manuscriptTitle":"Genetic and Clinical Characteristics of Japanese Cystinuria with Exon and Exon-Intron Boundary Variants","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-10-16 09:51:41","doi":"10.21203/rs.3.rs-4889642/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-11-25T05:26:22+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-11-23T23:18:33+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-11-20T17:35:24+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"236920881491877836639795401444403246460","date":"2024-11-14T10:47:52+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"93937118113304924372755227524032476257","date":"2024-11-13T12:43:37+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-10-21T08:23:08+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"192165447637782803197563608080442799698","date":"2024-10-16T09:52:19+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"111026247288575793473312929898929172422","date":"2024-10-15T17:24:27+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"68900500839697870576651320408741805504","date":"2024-09-11T07:04:16+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-09-05T21:31:14+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"339985571697397458861452665399367375436","date":"2024-08-26T14:29:52+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-08-26T01:28:11+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-08-26T01:25:38+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-08-24T10:29:01+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-08-24T10:24:54+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2024-08-10T02:40:19+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"44a33eb6-a8a7-4a7d-ac8e-55c5521c42bb","owner":[],"postedDate":"October 16th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":37992392,"name":"Biological sciences/Genetics/Genome/Genetic variation"},{"id":37992393,"name":"Health sciences/Nephrology/Kidney diseases/Renal calculi"}],"tags":[],"updatedAt":"2025-09-29T15:58:58+00:00","versionOfRecord":{"articleIdentity":"rs-4889642","link":"https://doi.org/10.1038/s41598-025-14240-4","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2025-09-26 15:56:59","publishedOnDateReadable":"September 26th, 2025"},"versionCreatedAt":"2024-10-16 09:51:41","video":"","vorDoi":"10.1038/s41598-025-14240-4","vorDoiUrl":"https://doi.org/10.1038/s41598-025-14240-4","workflowStages":[]},"version":"v1","identity":"rs-4889642","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4889642","identity":"rs-4889642","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}