UMOD Gene Mutations in Autosomal Dominant Tubulointerstitial Kidney Disease: First Cases Reported from Türkiye

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Ekici This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6895203/v1 This work is licensed under a CC BY 4.0 License Status: Under Revision Version 1 posted 13 You are reading this latest preprint version Abstract Background: Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD) is a rare hereditary disorder that typically presents with slowly progressive chronic kidney disease (CKD), bland urinary sediment, hyperuricemia, and early-onset gout. Mutations in the UMOD gene are the most common cause. However, clinical heterogeneity remains underappreciated, particularly in underrepresented populations. Methods: We investigated three unrelated families from the same village in Türkiye with a history of CKD of unknown etiology. A total of 56 individuals were screened using Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA) to identify pathogenic variants in UMOD , MUC1 , HNF1B , REN , and SEC61A1 genes. Results: A heterozygous missense variant in the UMOD gene (c.172G>A; p.Gly58Cys) was detected in 32 individuals. Among them, 14 had clinically confirmed CKD (mean age 60.9 years), and 18 were asymptomatic carriers (mean age 41.6 years). Notably, none of the affected individuals exhibited hyperuricemia or gout. This highlights considerable intrafamilial phenotypic variability and suggests that classical features may be absent even in genetically confirmed cases. Conclusion: To our knowledge, this is the first report of genetically confirmed ADTKD-UMOD cases from Türkiye. Our findings underscore the diagnostic value of genetic testing in familial CKD and demonstrate that UMOD -associated disease can manifest without hyperuricemia or gout. Increased awareness and early genetic screening are essential for accurate diagnosis and appropriate family counseling. Figures Figure 1 Figure 2 Figure 3 Introduction Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a genetic disorder characterized by autosomal dominant inheritance, primarily leading to progressive renal insufficiency. The disease manifests through tubulointerstitial nephropathy, which affects the kidney's tubular and interstitial regions, and is typically accompanied by bland urinary sediment, indicating an absence of significant inflammation. UMOD is the first identified and the most commonly mutated gene causing ADTKD, accounting for approximately 60% of ADTKD cases. Mutations in MUC1 , HNF1B , REN , and SEC61A1 have also been identified as causes of ADTKD( 1 , 2 ).A gene-based classification system for ADTKD has been introduced by Kidney Disease: Improving Global Outcomes (KDIGO). This system categorizes kidney disorders based on specific genetic mutations, allowing for more accurate diagnoses and personalized treatment approaches( 3 ). Awareness of ADTKD has increased with the widespread use of genetic testing, and it accounts for approximately 5% of monogenic chronic kidney disease patients( 2 ). The UMOD gene, located on chromosome 16p12, encodes uromodulin, which is produced in the thick ascending limb of the loop of Henle. Uromodulin is the most abundant glycoprotein in human urine and is rich in cysteine. Although the role of uromodulin has not yet been fully elucidated, it has been shown to be effective in maintaining water and electrolyte balance, preventing kidney stone formation by inhibiting calcium oxalate and calcium phosphate crystallization, and preventing urinary tract infections( 4 ). Abnormal accumulation of mutant uromodulin protein in the tubular cells results in tubular atrophy and progressive renal damage( 5 ). In patients with UMOD-associated ADTKD (ADTKD-UMOD), hyperuricemia and progressive chronic kidney disease (CKD) are usually predominant. Gout can occur at an early age. The progression of CKD is generally slow, and the average age for the development of end-stage renal disease (ESRD) is between 30 and 70 years, although the reason for this age range is not fully understood( 6 ). The prevalence of CKD in Türkiye is 15.7%, and the number of patients requiring renal replacement therapy due to ESRD is increasing( 7 ). Despite the availability of diagnostic tools, the rate of CKD with unknown etiology remains high both globally and in Türkiye reaching up to 10%. In this study, we present the genetic testing results and clinical findings of patients in our clinic who have CKD of unknown etiology, a family history of the disease, and no identifiable cause. Upon reviewing the patients' findings, we considered tubulointerstitial kidney disease as the cause due to the absence of proteinuria, lack of active urinary sediment, and slow progression of kidney disease. With these findings, ADTKD was considered. Although this group of patients did not have hyperuricemia or a history of gout, ADTKD-MUC was initially suspected; however, genetic analysis did not confirm this. Here, we will discuss the UMOD mutations identified in three families and their clinical characteristics. Our results highlight the importance of genetic testing in patients with a family history of CKD, where the etiology could not be fully elucidated with available tests. Materials and Methods Fourteen patients with CKD of unknown etiology, who were under follow-up in our clinic, were evaluated earlier. After mapping their family trees, we discovered that these patients – all residing in the same village–belonged to three distinct families. Our analysis was conducted on a total of 56 individuals, including the 14 patients.The creatinine, uric acid, urine analysis, and ultrasonography data of the patients were obtained from our preceding project. This study was conducted in accordance with the Declaration of Helsinki and was approved by the Local Ethics Committee and after receiving approval from the local ethics committee, the blood samples were sent to our partner laboratory for genetic analysis. SNV Analysis Direct Sanger sequencing of the MUC1 , UMOD , HNF1b , REN , SEC61A1 genes was performed as aroutine analysis in the accredited molecular genetics laboratories of theUniversity Clinics of Erlangen. Variants were detected using SeqPilot (JSI medical systems) and analyzed with themutation prediction software MutationTaster ( 8 ) and the Polyphen-2score ( 9 ). CNV Analysis For CNV analysis of copy number variants of the gene HNF1b we used the SALSAreagents and a predesigned kit (P241-D1 MODY, Kit-ID MRCH-41211) for MLPA –multiplex ligation-dependent probe amplification (MRC-Holland), accordingto the manufacturer’s instructions. SNaPshot minisequencing of MUC1 -VNTR To analyze the variant c.428dupC in the gene MUC1 we performed a primer-extension assay to detect the very rare event of a single duplication of C creating an eight base cytosine homopolymer stretch (8C) against a very high copy background of wild-type (7C) stretches in the VNTR of MUC1 ( 10 ). Results Genetic analysis was performed on a total of 56 individuals from 3 families, and mutations were detected in 32 of them. The average age of the 32 individuals with mutations was 32 ± 14 years, and 43.8% were female. The average age of our 14 CKD patients under follow-up was 60.92 years. Among the 7 patients who developed ESRD, 3 had undergone renal transplantation, while 4 were receiving hemodialysis. The average age of the patients who developed ESRD was 63.16 years. Initially, we performed MUC1 -VNTR analysis on three individuals from the same family, two of whom were being followed for CKD. The MUC1 c.428dupC mutation was not found in any of them. Subsequently, in one of our CKD patients, we conducted a copy number analysis of the HNF1B gene using the MLPA method and performed classical Sanger sequencing on the MUC1 , UMOD , HNF1B , REN , and SEC61A1 genes. A mutation in the UMOD gene (c.172G > A; p.Gly58Cys) was identified. To investigate the distribution of the identified mutation within the family, segregation analysis was performed on 56 individuals for the UMOD mutation mentioned in the methods section. The same mutation was detected in 14 of the CKD patients under follow-up. The mutation was also found in 18 individuals who had not previously been diagnosed with CKD, with an average age of 41.61 years. No mutations were detected in 23 individuals. Uric acide levels were 5.48 ± 1.98 mg/dl in 14 CKD patients with mutation, and 5.13 ± 1.19mg/dl in 18 patients with mutation .In patients with the mutation, proteinuria was not detected. Table 1 Phenotypic findings related to the mutation CKD with mutation (n:14) Healthy with mutation(n:18) Age 60,92 ± 12,14 41,61 ± 10,75 Gender (Female) 50% 38,9% Creatinine(mg/dl) 2.08 ± 1.26 0,76 ± 0,18 Uric acide (mg/dl) 5.48 ± 1.98 5.13 ± 1.19 Pedigrees were constructed based on clinical history and the results of genetic analyses. Individuals with a confirmed diagnosis of chronic kidney disease (CKD), including those who are deceased or who were found to carry the disease-causing mutation, are indicated by black symbols. Dark grey symbols represent individuals in whom the pathogenic mutation was detected despite no prior diagnosis of CKD. Light grey symbols denote family members for whom relevant information was obtained solely through family history (Fig. 1 , 2 , 3 ). Discussion In this study, a UMOD gene mutation (c.172G > A; p.Gly58Cys) was identified in 32 individuals from 3 families with a history of CKD of unknown etiology. To the best of our knowledge, this is the first study conducted in our country related to ADTKD. Since ADTKD does not have specific clinical or histological features, it is often underrecognized among physicians, and even when suspected, genetic testing is not usually available. It is difficult to speak of its exact prevalence; however, it is the most common cause of monogenic CKD. In a study involving 3315 CKD patients, 66 different monogenic disorders were identified, 3% of which were attributed to mutations in the UMOD gene( 10 ). In a study from Italy, UMOD mutations were found in 5 out of 911 kidney transplant patients with unknown renal disease etiology( 11 ). In a study conducted in the UK, ten different UMOD mutations were identified in 35 individuals from 18 families. These mutations accounted for 1% of patients with CKD stages 3–5, 2% of patients with end-stage renal disease (ESRD), 9% of hereditary kidney disease cases, and 56% of ADTKD cases( 12 ).In an Australian cohort study, a genetic diagnosis was identified in 25% of patients less than 50 years old and presenting with kidney failure of unknown etiology and most of them was ADTKD-UMOD ( 13 )More than 130 variants associated with ADTKD-UMOD have been identified, and pathogenic variants are most commonly concentrated in exons 3 and 4, affecting cysteine residues ( 14 , 15 ). The clinical features of ADTKD-UMOD include slowly progressive kidney damage, with most patients also exhibiting hyperuricemia and developing gout. In some series, gout has been detected in up to 65% of patients from an early age( 16 ). Hyperuricemia in ADTKD-UMOD is most likely due to increased urate reabsorption. Proteinuria may be absent or present at a mild level, and urinary sediment is bland. As the disease progresses, kidney size decreases, and renal cysts may develop. In a review by Moskowitz et al., 59 different UMOD mutations were evaluated in 202 patients from 74 families, and the median ages for hyperuricemia, gout, and ESRD were found to be 24, 40, and 56 years, respectively( 17 ). Hyperuricemia developed in 80% of patients, and gout was reported to occur in adolescent males. In our index cases, hyperuricemia and gout were absent, so genetic screening started with the MUC1 mutation, but when no mutation was found, we proceeded to test for other mutations. The UMOD mutation identified in our cases did not exhibit hyperuricemia or gout. In a study by Chun et al., a UMOD mutation was identified in 8 families initially suspected to have glomerular disease, and similar to our patients, neither hyperuricemia nor gout was observed(18). A recent study from the German Chronic Kidney Disease (GCKD) cohort showed that hereditary tubulointerstitial kidney diseases, particularly UMOD- ADTKD, are more common than previously recognized. Notably, many patients lacked typical features such as hyperuricemia or gout, aligning with our cohort. These findings reinforce the need for genetic testing in familial CKD cases of unknown origin, even when classical clinical signs are absent( 19 ).Thus, hyperuricemia and gout are not obligatory findings of the disease. The UMOD mutation was first described by Hart et al., who identified four different heterozygous mutations in exon 4 of the UMOD gene( 20 ). In a study conducted to better define the genetic and clinical findings of ADTKD-UMOD, 125 UMOD mutations were evaluated in 722 individuals from 249 families. Although the age of ESRD development varied based on the mutation, the average age was 47 years, ranging from 20 to 70 years. The study found that factors such as the presence of gout, the age of gout onset, the parental age of ESRD, and an in vitro score measuring the impact of the specific UMOD mutation on uromodulin trafficking were significantly correlated with kidney survival.They also noted better survival in females compared to males( 6 ). Similarly, in the study by Moskowitz et al., renal survival was found to be worse in males( 17 ). In another study of 109 patients with 37 different UMOD mutations, the average age for ESRD was found to be 54 years, with significant intrafamilial variability observed even among individuals with the same mutation( 21 ). In the UMOD mutation catalog, we found that another mutation had been previously identified at the same position as our mutation (c.G172T; p.Gly58Cys). The mutation we identified involves a G-to-A substitution in the DNA, but the resulting change in the protein is the same (Glycine-to-Cysteine). In our patients, the average age for ESRD was 63.16 years, with a range between 43 and 78 years. In 18 patients who had not previously been diagnosed with CKD, a mutation was identified, and their average age was 41.61 years (range 27–58), with no abnormality detected in their kidney function tests. We can also say that there was a high level of intrafamilial variability in the mutation found in our patients. Since ADTKD-UMOD does not present with specific clinical or histopathological features identifiable by kidney biopsy, biopsy is not used for diagnosis. Uromodulin localization analyses conducted on kidney biopsy samples from ADTKD-UMOD patients have shown a loss of typical protein signals at the apical plasma membrane of epithelial cells in the thick ascending limb (TAL) of the loop of Henle, with this protein accumulating in large intracellular clusters within the endoplasmic reticulum (ER). Electron microscopy analyses revealed the presence of fibrillar material, likely composed of mutant uromodulin, in the expanded ER( 22 , 23 ).Ekici and colleagues were the first to introduce the term ADTKD. They conducted 14 biopsies from 5 families with UMOD and MUC1 mutations and identified the characteristic histological features observed in kidney biopsies, which included early and severe interstitial fibrosis/tubular atrophy, varying degrees of nephrosclerosis, arteriolar thickening and hyalinosis, as well as negative immunofluorescence or immunostaining (24,25). Since we did not observe active urinary sediment or proteinuria in our patients, we did not perform kidney biopsies. Genetic causes are now widely recognized as a major contributor to chronic kidney disease. With the increasing number of cases reported globally, ADTKD-UMOD has emerged as one of the most prevalent monogenic causes of CKD in adults.ADTKD-UMOD shows variability in both the age of onset and clinical manifestations, including hyperuricemia and early signs of gout both among families and within individual families. Despite these differences, most patients progress to CKD between their 30s and 50s. Declarations Data Availability: The UMOD c.172G>A (p.Gly58Ser) variant identified in this study has been submitted to and accepted by ClinVar , and is available under the accession number VCV001709460.4. Authors' contributions: Ayca Inci,Funda Sarı,Veysel Inci, Zülayha Öğür : Data collection, manuscript writing, clinical evaluation. Arif B. Ekici:Genetic analysis and interpretation. All authors read and approved the final manuscript. Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Ethics approval and consent to participate : This study was conducted in accordance with the principles of the Declaration of Helsinki . Ethical approval was obtained from the Ethics Committee of Antalya Training and Research Hospital with protocol number 4/10, dated 22.02.2018 Written informed consent was obtained from all participants and/or their legal guardians, where applicable. Consent for publication Written informed consent for publication of clinical data and genetic information was obtained from all individuals and/or their legal representatives. Competing interests The authors declare that they have no competing interests. References Olinger E, Hofmann P, Kidd K, et al. Clinical and genetic spectra of autosomal dominant tubulointerstitial kidney disease due to mutations in UMOD and MUC1. Kidney Int. 2020;98(3):717–31. Mabillard H, Sayer JA, Olinger E, et al. Clinical and genetic spectra of autosomal dominant tubulointerstitial kidney disease. Nephrol Dial Transpl. 2023;38(2):271–82. KDIGO. Autosomal dominant tubulointerstitial kidney disease: diagnosis, classification, and management—A KDIGO consensus report. Ekici AB, Hackenbeck T, Morinière V, et al. Uromodulin-related autosomal-dominant tubulointerstitial kidney disease—pathogenetic insights based on a case. Kidney Int. 2014;86(3):589–99. Zaucke F, Boettger T, Büttner M, et al. Mutant tamm-horsfall glycoprotein accumulation in endoplasmic reticulum induces apoptosis reversed by colchicine and sodium 4-phenylbutyrate. Hum Mol Genet. 2005;14(21):3169–78. Trudu M, Janas S, Lanzani C, et al. Genetic and clinical predictors of age of ESKD in individuals with autosomal dominant tubulointerstitial kidney disease due to UMOD mutations. Kidney Int. 2020;98(6):1600–9. Suleymanlar G, Arinsoy T, Altiparmak MR, et al. A population-based survey of Chronic REnal Disease In Turkey—the CREDIT study. Nephrol Dial Transpl. 2011;26(6):1862–71. Schwarz JM, Rodelsperger C, Schuelke M, et al. MutationTaster evaluates disease-causing potential of sequence alterations. Nat Methods. 2010;7(8):575–6. Adzhubei IA, Schmidt S, Peshkin L, et al. A method and server for predicting damaging missense mutations. Nat Methods. 2010;7(4):248–9. Groopman EE, Marasa M, Cameron-Christie S, et al. Diagnostic utility of exome sequencing for kidney disease. N Engl J Med. 2019;380(2):142–51. Bullich G, Domingo-Gallego A, Vargas I, et al. Unexpectedly high prevalence of rare genetic disorders in kidney transplant recipients with an unknown causal nephropathy. Genet Med. 2021;23(4):764–72. Bleyer AJ, Kmoch S, Antignac C, et al. Autosomal dominant tubulointerstitial kidney disease-UMOD is the most frequent non polycystic genetic kidney disease. Kidney Int. 2017;91(4):949–56. Stark Z, Schofield D, Martyn M, et al. Genomic testing in patients with kidney failure of an unknown cause: a national Australian study. Genet Med. 2022;24(4):919–27. Zhou J, Yao Y, Zhang X, et al. Autosomal dominant tubulointerstitial kidney disease—uromodulin misclassified as focal segmental glomerulosclerosis or hereditary glomerular disease. Kidney Blood Press Res. 2022;47(1):61–71. Smith C, Johnson DW, Sayer JA, et al. Autosomal dominant tubulointerstitial kidney disease: an emerging cause of genetic CKD. Kidney Int Rep. 2020;5(11):1631–41. Devuyst O, Olinger E, Rampoldi L, et al. Uromodulin storage diseases: clinical aspects and mechanisms. Nat Rev Nephrol. 2017;13(9):521–35. Moskowitz D, Rouse RC, Sakati N Association between genotype and phenotype in uromodulin-associated kidney disease. Nephron Clin Pract., Chun J, Kwon YE, Han SS et al. Autosomal dominant tubulointerstitial kidney disease caused by UMOD mutations misdiagnosed as glomerular diseases. Kidney Res Clin Pract. 2020;39(1):72–79. Popp B, Ekici AB, Knaup KX, et al. Prevalence of hereditary tubulointerstitial kidney diseases in the German Chronic Kidney Disease study. Eur J Hum Genet. 2022;30(12):1413–22. Hart TC, Gorry MC, Hart PS, et al. Mutations of the UMOD gene are responsible for medullary cystic kidney disease 2 and familial juvenile hyperuricemic nephropathy. J Med Genet. 2002;39(12):882–92. Bollee G, Dahan K, Flamant M, et al. Phenotype and outcome in hereditary tubulointerstitial nephritis secondary to UMOD mutations. Clin J Am Soc Nephrol. 2011;6(9):2429–38. Vylet’al P, Hodanova K, Fischer M, et al. Alterations of uromodulin biology: a common denominator of the genetically heterogeneous FJHN/MCKD syndrome. Kidney Int. 2006;70(6):1155–69. Nasr SH, Lucia JP, Galgano SJ, et al. Uromodulin storage disease. Kidney Int. 2008;73(8):971–6. Ekici AB, Hackenbeck T, Morinière V, et al. Renal fibrosis is the common feature of autosomal dominant tubulointerstitial kidney diseases caused by mutations in MUC1 or uromodulin. Kidney Int. 2014;86(3):589–99. Ekici AB, Hackenbeck T, Morinière V, Pannes A, Buettner M, Uebe S, et al. Renal fibrosis and impaired angiogenesis in autosomal dominant tubulointerstitial kidney disease. Orphanet. J Rare Dis. 2017;12(1):50. Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6895203","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":502596266,"identity":"0c1aaefe-ef93-4d3c-a7da-866f8c6854a4","order_by":0,"name":"Ayca Inci","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABB0lEQVRIiWNgGAWjYLCCBAYGHn5mxgaDjw0gLmPjAaK0SLY3Hyic2cAgAdTSQFgLCBicOZbwmReshYEBrxb+GckPPzzcYSfDcCPHcLPtDps63fbDQFtqbKJxaZG4kWYskXgmmYdxRo6xce6ZNAmzM4lALcfSchtw6bmRwyCR2HaAh1kix8w4t+2whNkBoBbGhsM4tcjfyGH+AdLCJpFj/tsSpOX8Q/xaDG7ksIFt4eE5lmDMCNJyg4AthmeemVkktiXzSLA3HzDsbUuT3HYDaEsCHr/IHU9+fPNnm529/WFgVP5ss+E3O5/+8MGHGhvc3hdIwCaKVRAG+A/gkx0Fo2AUjIJRAAQA0UhkNgnIpYEAAAAASUVORK5CYII=","orcid":"","institution":"Antalya Eğitim ve Araştırma Hastanesi","correspondingAuthor":true,"prefix":"","firstName":"Ayca","middleName":"","lastName":"Inci","suffix":""},{"id":502596267,"identity":"caf0e2ab-0989-4cae-8244-620d141abf80","order_by":1,"name":"Funda Sarı","email":"","orcid":"","institution":"Akdeniz University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Funda","middleName":"","lastName":"Sarı","suffix":""},{"id":502596268,"identity":"7ac932bf-0274-4caf-96cd-ab7cbe2fc3e8","order_by":2,"name":"Veysel İnci","email":"","orcid":"","institution":"Kepez State Hospital","correspondingAuthor":false,"prefix":"","firstName":"Veysel","middleName":"","lastName":"İnci","suffix":""},{"id":502596269,"identity":"5bf97f90-d664-4023-818a-50b06babffb1","order_by":3,"name":"Züleyha Öğür","email":"","orcid":"","institution":"ANTALYA PROVINCIAL HEALTH DIRECTORATE","correspondingAuthor":false,"prefix":"","firstName":"Züleyha","middleName":"","lastName":"Öğür","suffix":""},{"id":502596270,"identity":"ca4ab98e-b71c-4b44-925a-c51f55b11803","order_by":4,"name":"Arif B. Ekici","email":"","orcid":"","institution":"Friedrich-Alexander-Universität","correspondingAuthor":false,"prefix":"","firstName":"Arif","middleName":"B.","lastName":"Ekici","suffix":""}],"badges":[],"createdAt":"2025-06-14 17:23:17","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6895203/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6895203/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":89593241,"identity":"93ebc0cd-81a1-4f55-93a9-59922b077f72","added_by":"auto","created_at":"2025-08-21 16:19:35","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":113398,"visible":true,"origin":"","legend":"\u003cp\u003ePedigree of Family 1\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-6895203/v1/f13488e65b41e5ea234b20d3.jpeg"},{"id":89592060,"identity":"27d311b6-5321-4079-ae08-64be2ec70b38","added_by":"auto","created_at":"2025-08-21 16:11:35","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":46874,"visible":true,"origin":"","legend":"\u003cp\u003ePedigree of Family 2\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-6895203/v1/b81a691017f96d5971a71d3b.jpeg"},{"id":89592070,"identity":"7affe065-9984-4c4e-9d0d-4d964442693a","added_by":"auto","created_at":"2025-08-21 16:11:35","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":119081,"visible":true,"origin":"","legend":"\u003cp\u003ePedigree of Family 3\u003c/p\u003e","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-6895203/v1/e91e23a04107514d1dcf894d.jpeg"},{"id":89594326,"identity":"41550384-fc04-477a-b73d-db91308af23f","added_by":"auto","created_at":"2025-08-21 16:27:35","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":712662,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6895203/v1/6ff2e39f-a73b-4af5-922e-8cbf2c17a029.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"UMOD Gene Mutations in Autosomal Dominant Tubulointerstitial Kidney Disease: First Cases Reported from Türkiye","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAutosomal dominant tubulointerstitial kidney disease (ADTKD) is a genetic disorder characterized by autosomal dominant inheritance, primarily leading to progressive renal insufficiency. The disease manifests through tubulointerstitial nephropathy, which affects the kidney's tubular and interstitial regions, and is typically accompanied by bland urinary sediment, indicating an absence of significant inflammation. UMOD is the first identified and the most commonly mutated gene causing ADTKD, accounting for approximately 60% of ADTKD cases. Mutations in \u003cem\u003eMUC1\u003c/em\u003e, \u003cem\u003eHNF1B\u003c/em\u003e, \u003cem\u003eREN\u003c/em\u003e, and \u003cem\u003eSEC61A1\u003c/em\u003e have also been identified as causes of ADTKD(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e).A gene-based classification system for ADTKD has been introduced by Kidney Disease: Improving Global Outcomes (KDIGO). This system categorizes kidney disorders based on specific genetic mutations, allowing for more accurate diagnoses and personalized treatment approaches(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eAwareness of ADTKD has increased with the widespread use of genetic testing, and it accounts for approximately 5% of monogenic chronic kidney disease patients(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). The \u003cem\u003eUMOD\u003c/em\u003e gene, located on chromosome 16p12, encodes uromodulin, which is produced in the thick ascending limb of the loop of Henle. Uromodulin is the most abundant glycoprotein in human urine and is rich in cysteine. Although the role of uromodulin has not yet been fully elucidated, it has been shown to be effective in maintaining water and electrolyte balance, preventing kidney stone formation by inhibiting calcium oxalate and calcium phosphate crystallization, and preventing urinary tract infections(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Abnormal accumulation of mutant uromodulin protein in the tubular cells results in tubular atrophy and progressive renal damage(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). In patients with UMOD-associated ADTKD (ADTKD-UMOD), hyperuricemia and progressive chronic kidney disease (CKD) are usually predominant. Gout can occur at an early age. The progression of CKD is generally slow, and the average age for the development of end-stage renal disease (ESRD) is between 30 and 70 years, although the reason for this age range is not fully understood(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). The prevalence of CKD in T\u0026uuml;rkiye is 15.7%, and the number of patients requiring renal replacement therapy due to ESRD is increasing(\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Despite the availability of diagnostic tools, the rate of CKD with unknown etiology remains high both globally and in T\u0026uuml;rkiye reaching up to 10%.\u003c/p\u003e\u003cp\u003eIn this study, we present the genetic testing results and clinical findings of patients in our clinic who have CKD of unknown etiology, a family history of the disease, and no identifiable cause. Upon reviewing the patients' findings, we considered tubulointerstitial kidney disease as the cause due to the absence of proteinuria, lack of active urinary sediment, and slow progression of kidney disease. With these findings, ADTKD was considered. Although this group of patients did not have hyperuricemia or a history of gout, ADTKD-MUC was initially suspected; however, genetic analysis did not confirm this. Here, we will discuss the UMOD mutations identified in three families and their clinical characteristics. Our results highlight the importance of genetic testing in patients with a family history of CKD, where the etiology could not be fully elucidated with available tests.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003eFourteen patients with CKD of unknown etiology, who were under follow-up in our clinic, were evaluated earlier. After mapping their family trees, we discovered that these patients \u0026ndash; all residing in the same village\u0026ndash;belonged to three distinct families. Our analysis was conducted on a total of 56 individuals, including the 14 patients.The creatinine, uric acid, urine analysis, and ultrasonography data of the patients were obtained from our preceding project. This study was conducted in accordance with the Declaration of Helsinki and was approved by the Local Ethics Committee and after receiving approval from the local ethics committee, the blood samples were sent to our partner laboratory for genetic analysis.\u003c/p\u003e\u003cp\u003eSNV Analysis\u003c/p\u003e\u003cp\u003eDirect Sanger sequencing of the \u003cem\u003eMUC1\u003c/em\u003e, \u003cem\u003eUMOD\u003c/em\u003e, \u003cem\u003eHNF1b\u003c/em\u003e, \u003cem\u003eREN\u003c/em\u003e, \u003cem\u003eSEC61A1\u003c/em\u003e genes was performed as aroutine analysis in the accredited molecular genetics laboratories of theUniversity Clinics of Erlangen. Variants were detected using SeqPilot (JSI medical systems) and analyzed with themutation prediction software MutationTaster (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e) and the Polyphen-2score (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eCNV Analysis\u003c/p\u003e\u003cp\u003eFor CNV analysis of copy number variants of the gene \u003cem\u003eHNF1b\u003c/em\u003ewe used the SALSAreagents and a predesigned kit (P241-D1 MODY, Kit-ID MRCH-41211) for MLPA \u0026ndash;multiplex ligation-dependent probe amplification (MRC-Holland), accordingto the manufacturer\u0026rsquo;s instructions.\u003c/p\u003e\u003cp\u003eSNaPshot minisequencing of \u003cem\u003eMUC1\u003c/em\u003e-VNTR\u003c/p\u003e\u003cp\u003eTo analyze the variant c.428dupC in the gene \u003cem\u003eMUC1\u003c/em\u003e we performed a primer-extension assay to detect the very rare event of a single duplication of C creating an eight base cytosine homopolymer stretch (8C) against a very high copy background of wild-type (7C) stretches in the VNTR of \u003cem\u003eMUC1\u003c/em\u003e(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eGenetic analysis was performed on a total of 56 individuals from 3 families, and mutations were detected in 32 of them. The average age of the 32 individuals with mutations was 32\u0026thinsp;\u0026plusmn;\u0026thinsp;14 years, and 43.8% were female. The average age of our 14 CKD patients under follow-up was 60.92 years. Among the 7 patients who developed ESRD, 3 had undergone renal transplantation, while 4 were receiving hemodialysis. The average age of the patients who developed ESRD was 63.16 years.\u003c/p\u003e\u003cp\u003eInitially, we performed \u003cem\u003eMUC1\u003c/em\u003e-VNTR analysis on three individuals from the same family, two of whom were being followed for CKD. The \u003cem\u003eMUC1\u003c/em\u003e c.428dupC mutation was not found in any of them. Subsequently, in one of our CKD patients, we conducted a copy number analysis of the \u003cem\u003eHNF1B\u003c/em\u003e gene using the MLPA method and performed classical Sanger sequencing on the \u003cem\u003eMUC1\u003c/em\u003e, \u003cem\u003eUMOD\u003c/em\u003e, \u003cem\u003eHNF1B\u003c/em\u003e, \u003cem\u003eREN\u003c/em\u003e, and \u003cem\u003eSEC61A1\u003c/em\u003e genes. A mutation in the \u003cem\u003eUMOD\u003c/em\u003e gene (c.172G\u0026thinsp;\u0026gt;\u0026thinsp;A; p.Gly58Cys) was identified.\u003c/p\u003e\u003cp\u003eTo investigate the distribution of the identified mutation within the family, segregation analysis was performed on 56 individuals for the \u003cem\u003eUMOD\u003c/em\u003e mutation mentioned in the methods section. The same mutation was detected in 14 of the CKD patients under follow-up. The mutation was also found in 18 individuals who had not previously been diagnosed with CKD, with an average age of 41.61 years. No mutations were detected in 23 individuals. Uric acide levels were 5.48\u0026thinsp;\u0026plusmn;\u0026thinsp;1.98 mg/dl in 14 CKD patients with mutation, and 5.13\u0026thinsp;\u0026plusmn;\u0026thinsp;1.19mg/dl in 18 patients with mutation .In patients with the mutation, proteinuria was not detected.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003ePhenotypic findings related to the mutation\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"3\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCKD with mutation (n:14)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eHealthy with mutation(n:18)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e60,92\u0026thinsp;\u0026plusmn;\u0026thinsp;12,14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e41,61\u0026thinsp;\u0026plusmn;\u0026thinsp;10,75\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGender (Female)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e50%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e38,9%\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCreatinine(mg/dl)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.08\u0026thinsp;\u0026plusmn;\u0026thinsp;1.26\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0,76\u0026thinsp;\u0026plusmn;\u0026thinsp;0,18\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUric acide (mg/dl)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5.48\u0026thinsp;\u0026plusmn;\u0026thinsp;1.98\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5.13\u0026thinsp;\u0026plusmn;\u0026thinsp;1.19\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003ePedigrees were constructed based on clinical history and the results of genetic analyses. Individuals with a confirmed diagnosis of chronic kidney disease (CKD), including those who are deceased or who were found to carry the disease-causing mutation, are indicated by black symbols. Dark grey symbols represent individuals in whom the pathogenic mutation was detected despite no prior diagnosis of CKD. Light grey symbols denote family members for whom relevant information was obtained solely through family history (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e,\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e,\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this study, a \u003cem\u003eUMOD\u003c/em\u003e gene mutation (c.172G\u0026thinsp;\u0026gt;\u0026thinsp;A; p.Gly58Cys) was identified in 32 individuals from 3 families with a history of CKD of unknown etiology. To the best of our knowledge, this is the first study conducted in our country related to ADTKD. Since ADTKD does not have specific clinical or histological features, it is often underrecognized among physicians, and even when suspected, genetic testing is not usually available. It is difficult to speak of its exact prevalence; however, it is the most common cause of monogenic CKD. In a study involving 3315 CKD patients, 66 different monogenic disorders were identified, 3% of which were attributed to mutations in the \u003cem\u003eUMOD\u003c/em\u003e gene(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). In a study from Italy, \u003cem\u003eUMOD\u003c/em\u003e mutations were found in 5 out of 911 kidney transplant patients with unknown renal disease etiology(\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). In a study conducted in the UK, ten different \u003cem\u003eUMOD\u003c/em\u003e mutations were identified in 35 individuals from 18 families. These mutations accounted for 1% of patients with CKD stages 3\u0026ndash;5, 2% of patients with end-stage renal disease (ESRD), 9% of hereditary kidney disease cases, and 56% of ADTKD cases(\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e).In an Australian cohort study, a genetic diagnosis was identified in 25% of patients less than 50 years old and presenting with kidney failure of unknown etiology and most of them was ADTKD-UMOD (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e)More than 130 variants associated with ADTKD-UMOD have been identified, and pathogenic variants are most commonly concentrated in exons 3 and 4, affecting cysteine residues (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThe clinical features of ADTKD-UMOD include slowly progressive kidney damage, with most patients also exhibiting hyperuricemia and developing gout. In some series, gout has been detected in up to 65% of patients from an early age(\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). Hyperuricemia in ADTKD-UMOD is most likely due to increased urate reabsorption. Proteinuria may be absent or present at a mild level, and urinary sediment is bland. As the disease progresses, kidney size decreases, and renal cysts may develop. In a review by Moskowitz et al., 59 different \u003cem\u003eUMOD\u003c/em\u003emutations were evaluated in 202 patients from 74 families, and the median ages for hyperuricemia, gout, and ESRD were found to be 24, 40, and 56 years, respectively(\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). Hyperuricemia developed in 80% of patients, and gout was reported to occur in adolescent males. In our index cases, hyperuricemia and gout were absent, so genetic screening started with the \u003cem\u003eMUC1\u003c/em\u003e mutation, but when no mutation was found, we proceeded to test for other mutations. The \u003cem\u003eUMOD\u003c/em\u003e mutation identified in our cases did not exhibit hyperuricemia or gout. In a study by Chun et al., a \u003cem\u003eUMOD\u003c/em\u003e mutation was identified in 8 families initially suspected to have glomerular disease, and similar to our patients, neither hyperuricemia nor gout was observed(18). A recent study from the German Chronic Kidney Disease (GCKD) cohort showed that hereditary tubulointerstitial kidney diseases, particularly UMOD- ADTKD, are more common than previously recognized. Notably, many patients lacked typical features such as hyperuricemia or gout, aligning with our cohort. These findings reinforce the need for genetic testing in familial CKD cases of unknown origin, even when classical clinical signs are absent(\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e19\u003c/span\u003e).Thus, hyperuricemia and gout are not obligatory findings of the disease.\u003c/p\u003e\u003cp\u003eThe \u003cem\u003eUMOD\u003c/em\u003e mutation was first described by Hart et al., who identified four different heterozygous mutations in exon 4 of the \u003cem\u003eUMOD\u003c/em\u003e gene(\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e20\u003c/span\u003e). In a study conducted to better define the genetic and clinical findings of ADTKD-UMOD, 125 \u003cem\u003eUMOD\u003c/em\u003e mutations were evaluated in 722 individuals from 249 families. Although the age of ESRD development varied based on the mutation, the average age was 47 years, ranging from 20 to 70 years. The study found that factors such as the presence of gout, the age of gout onset, the parental age of ESRD, and an in vitro score measuring the impact of the specific \u003cem\u003eUMOD\u003c/em\u003e mutation on uromodulin trafficking were significantly correlated with kidney survival.They also noted better survival in females compared to males(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Similarly, in the study by Moskowitz et al., renal survival was found to be worse in males(\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). In another study of 109 patients with 37 different \u003cem\u003eUMOD\u003c/em\u003e mutations, the average age for ESRD was found to be 54 years, with significant intrafamilial variability observed even among individuals with the same mutation(\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e21\u003c/span\u003e). In the \u003cem\u003eUMOD\u003c/em\u003e mutation catalog, we found that another mutation had been previously identified at the same position as our mutation (c.G172T; p.Gly58Cys). The mutation we identified involves a G-to-A substitution in the DNA, but the resulting change in the protein is the same (Glycine-to-Cysteine). In our patients, the average age for ESRD was 63.16 years, with a range between 43 and 78 years. In 18 patients who had not previously been diagnosed with CKD, a mutation was identified, and their average age was 41.61 years (range 27\u0026ndash;58), with no abnormality detected in their kidney function tests. We can also say that there was a high level of intrafamilial variability in the mutation found in our patients.\u003c/p\u003e\u003cp\u003eSince ADTKD-UMOD does not present with specific clinical or histopathological features identifiable by kidney biopsy, biopsy is not used for diagnosis. Uromodulin localization analyses conducted on kidney biopsy samples from ADTKD-UMOD patients have shown a loss of typical protein signals at the apical plasma membrane of epithelial cells in the thick ascending limb (TAL) of the loop of Henle, with this protein accumulating in large intracellular clusters within the endoplasmic reticulum (ER). Electron microscopy analyses revealed the presence of fibrillar material, likely composed of mutant uromodulin, in the expanded ER(\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e23\u003c/span\u003e).Ekici and colleagues were the first to introduce the term ADTKD. They conducted 14 biopsies from 5 families with UMOD and MUC1 mutations and identified the characteristic histological features observed in kidney biopsies, which included early and severe interstitial fibrosis/tubular atrophy, varying degrees of nephrosclerosis, arteriolar thickening and hyalinosis, as well as negative immunofluorescence or immunostaining (24,25). Since we did not observe active urinary sediment or proteinuria in our patients, we did not perform kidney biopsies.\u003c/p\u003e\u003cp\u003eGenetic causes are now widely recognized as a major contributor to chronic kidney disease. With the increasing number of cases reported globally, ADTKD-UMOD has emerged as one of the most prevalent monogenic causes of CKD in adults.ADTKD-UMOD shows variability in both the age of onset and clinical manifestations, including hyperuricemia and early signs of gout both among families and within individual families. Despite these differences, most patients progress to CKD between their 30s and 50s.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData Availability:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe \u003cstrong\u003eUMOD c.172G\u0026gt;A (p.Gly58Ser)\u003c/strong\u003e variant identified in this study has been submitted to and accepted by \u003cstrong\u003eClinVar\u003c/strong\u003e\u003cstrong\u003e,\u003c/strong\u003e and is available under the accession number \u0026nbsp; VCV001709460.4.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAyca Inci,Funda Sarı,Veysel Inci, Z\u0026uuml;layha \u0026Ouml;ğ\u0026uuml;r\u003c/strong\u003e\u003cstrong\u003e:\u003c/strong\u003e Data collection, manuscript writing, clinical evaluation.\u003c/p\u003e\n\u003cp\u003eArif B. Ekici:Genetic analysis and interpretation.\u003c/p\u003e\n\u003cp\u003eAll authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003eFunding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003eEthics approval and consent to participate : This study was conducted in accordance with the principles of the \u003cstrong\u003eDeclaration of Helsinki\u003c/strong\u003e. Ethical approval was obtained from the Ethics Committee of Antalya Training and Research Hospital with protocol number 4/10, dated 22.02.2018 \u0026nbsp;Written informed consent was obtained from all participants and/or their legal guardians, where applicable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent for publication of clinical data and genetic information was obtained from all individuals and/or their legal representatives.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eOlinger E, Hofmann P, Kidd K, et al. Clinical and genetic spectra of autosomal dominant tubulointerstitial kidney disease due to mutations in UMOD and MUC1. Kidney Int. 2020;98(3):717\u0026ndash;31.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMabillard H, Sayer JA, Olinger E, et al. Clinical and genetic spectra of autosomal dominant tubulointerstitial kidney disease. Nephrol Dial Transpl. 2023;38(2):271\u0026ndash;82.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKDIGO. Autosomal dominant tubulointerstitial kidney disease: diagnosis, classification, and management\u0026mdash;A KDIGO consensus report.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eEkici AB, Hackenbeck T, Morini\u0026egrave;re V, et al. Uromodulin-related autosomal-dominant tubulointerstitial kidney disease\u0026mdash;pathogenetic insights based on a case. Kidney Int. 2014;86(3):589\u0026ndash;99.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eZaucke F, Boettger T, B\u0026uuml;ttner M, et al. Mutant tamm-horsfall glycoprotein accumulation in endoplasmic reticulum induces apoptosis reversed by colchicine and sodium 4-phenylbutyrate. Hum Mol Genet. 2005;14(21):3169\u0026ndash;78.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTrudu M, Janas S, Lanzani C, et al. Genetic and clinical predictors of age of ESKD in individuals with autosomal dominant tubulointerstitial kidney disease due to UMOD mutations. Kidney Int. 2020;98(6):1600\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSuleymanlar G, Arinsoy T, Altiparmak MR, et al. A population-based survey of Chronic REnal Disease In Turkey\u0026mdash;the CREDIT study. Nephrol Dial Transpl. 2011;26(6):1862\u0026ndash;71.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSchwarz JM, Rodelsperger C, Schuelke M, et al. MutationTaster evaluates disease-causing potential of sequence alterations. Nat Methods. 2010;7(8):575\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAdzhubei IA, Schmidt S, Peshkin L, et al. A method and server for predicting damaging missense mutations. Nat Methods. 2010;7(4):248\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGroopman EE, Marasa M, Cameron-Christie S, et al. Diagnostic utility of exome sequencing for kidney disease. N Engl J Med. 2019;380(2):142\u0026ndash;51.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBullich G, Domingo-Gallego A, Vargas I, et al. Unexpectedly high prevalence of rare genetic disorders in kidney transplant recipients with an unknown causal nephropathy. Genet Med. 2021;23(4):764\u0026ndash;72.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBleyer AJ, Kmoch S, Antignac C, et al. Autosomal dominant tubulointerstitial kidney disease-UMOD is the most frequent non polycystic genetic kidney disease. Kidney Int. 2017;91(4):949\u0026ndash;56.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eStark Z, Schofield D, Martyn M, et al. Genomic testing in patients with kidney failure of an unknown cause: a national Australian study. Genet Med. 2022;24(4):919\u0026ndash;27.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eZhou J, Yao Y, Zhang X, et al. Autosomal dominant tubulointerstitial kidney disease\u0026mdash;uromodulin misclassified as focal segmental glomerulosclerosis or hereditary glomerular disease. Kidney Blood Press Res. 2022;47(1):61\u0026ndash;71.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSmith C, Johnson DW, Sayer JA, et al. Autosomal dominant tubulointerstitial kidney disease: an emerging cause of genetic CKD. Kidney Int Rep. 2020;5(11):1631\u0026ndash;41.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDevuyst O, Olinger E, Rampoldi L, et al. Uromodulin storage diseases: clinical aspects and mechanisms. Nat Rev Nephrol. 2017;13(9):521\u0026ndash;35.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMoskowitz D, Rouse RC, Sakati N Association between genotype and phenotype in uromodulin-associated kidney disease. Nephron Clin Pract., Chun J, Kwon YE, Han SS et al. Autosomal dominant tubulointerstitial kidney disease caused by UMOD mutations misdiagnosed as glomerular diseases. \u003cem\u003eKidney Res Clin Pract. 2020;39(1):72\u0026ndash;79.\u003c/em\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePopp B, Ekici AB, Knaup KX, et al. Prevalence of hereditary tubulointerstitial kidney diseases in the German Chronic Kidney Disease study. Eur J Hum Genet. 2022;30(12):1413\u0026ndash;22.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHart TC, Gorry MC, Hart PS, et al. Mutations of the UMOD gene are responsible for medullary cystic kidney disease 2 and familial juvenile hyperuricemic nephropathy. J Med Genet. 2002;39(12):882\u0026ndash;92.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBollee G, Dahan K, Flamant M, et al. Phenotype and outcome in hereditary tubulointerstitial nephritis secondary to UMOD mutations. Clin J Am Soc Nephrol. 2011;6(9):2429\u0026ndash;38.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eVylet\u0026rsquo;al P, Hodanova K, Fischer M, et al. Alterations of uromodulin biology: a common denominator of the genetically heterogeneous FJHN/MCKD syndrome. Kidney Int. 2006;70(6):1155\u0026ndash;69.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNasr SH, Lucia JP, Galgano SJ, et al. Uromodulin storage disease. Kidney Int. 2008;73(8):971\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eEkici AB, Hackenbeck T, Morini\u0026egrave;re V, et al. Renal fibrosis is the common feature of autosomal dominant tubulointerstitial kidney diseases caused by mutations in MUC1 or uromodulin. Kidney Int. 2014;86(3):589\u0026ndash;99.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eEkici AB, Hackenbeck T, Morini\u0026egrave;re V, Pannes A, Buettner M, Uebe S, et al. \u003cem\u003eRenal fibrosis and impaired angiogenesis in autosomal dominant tubulointerstitial kidney disease.\u003c/em\u003eOrphanet. J Rare Dis. 2017;12(1):50.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bnep","sideBox":"Learn more about [BMC Nephrology](http://bmcnephrol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bnep/default.aspx","title":"BMC Nephrology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-6895203/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6895203/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e\u003cbr\u003e\nAutosomal Dominant Tubulointerstitial Kidney Disease (ADTKD) is a rare hereditary disorder that typically presents with slowly progressive chronic kidney disease (CKD), bland urinary sediment, hyperuricemia, and early-onset gout. Mutations in the \u003cem\u003eUMOD\u003c/em\u003e gene are the most common cause. However, clinical heterogeneity remains underappreciated, particularly in underrepresented populations.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e\u003cbr\u003e\nWe investigated three unrelated families from the same village in Türkiye with a history of CKD of unknown etiology. A total of 56 individuals were screened using Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA) to identify pathogenic variants in \u003cem\u003eUMOD\u003c/em\u003e, \u003cem\u003eMUC1\u003c/em\u003e, \u003cem\u003eHNF1B\u003c/em\u003e, \u003cem\u003eREN\u003c/em\u003e, and \u003cem\u003eSEC61A1\u003c/em\u003e genes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e\u003cbr\u003e\nA heterozygous missense variant in the \u003cem\u003eUMOD\u003c/em\u003e gene (c.172G\u0026gt;A; p.Gly58Cys) was detected in 32 individuals. Among them, 14 had clinically confirmed CKD (mean age 60.9 years), and 18 were asymptomatic carriers (mean age 41.6 years). Notably, none of the affected individuals exhibited hyperuricemia or gout. This highlights considerable intrafamilial phenotypic variability and suggests that classical features may be absent even in genetically confirmed cases.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e\u003cbr\u003e\nTo our knowledge, this is the first report of genetically confirmed ADTKD-UMOD cases from Türkiye. Our findings underscore the diagnostic value of genetic testing in familial CKD and demonstrate that \u003cem\u003eUMOD\u003c/em\u003e-associated disease can manifest without hyperuricemia or gout. Increased awareness and early genetic screening are essential for accurate diagnosis and appropriate family counseling.\u003c/p\u003e","manuscriptTitle":"UMOD Gene Mutations in Autosomal Dominant Tubulointerstitial Kidney Disease: First Cases Reported from Türkiye","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-21 16:11:31","doi":"10.21203/rs.3.rs-6895203/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-04-30T16:12:49+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-08T21:05:54+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-08T03:29:52+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"294615989770111069007067956884989279805","date":"2026-03-25T23:34:41+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"44544735992273240478243876687499971250","date":"2026-03-25T17:26:50+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"56004506437919735582526073174442541502","date":"2026-03-25T11:47:04+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-19T13:26:14+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"82699415357341902624387822589384606727","date":"2025-08-15T18:47:27+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-08-13T18:45:01+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-08-12T11:48:22+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-08-12T10:27:22+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-08-11T17:45:54+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Nephrology","date":"2025-08-11T17:43:16+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bnep","sideBox":"Learn more about [BMC Nephrology](http://bmcnephrol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bnep/default.aspx","title":"BMC Nephrology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"6cd86b4b-0dee-48db-87ee-6e44699b1add","owner":[],"postedDate":"August 21st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"in-revision","subjectAreas":[],"tags":[],"updatedAt":"2026-04-30T16:24:51+00:00","versionOfRecord":[],"versionCreatedAt":"2025-08-21 16:11:31","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6895203","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6895203","identity":"rs-6895203","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}