Contrasting LRP5 Mutations in Osteoporosis-Pseudoglioma Syndrome and Osteopetrosis: Case Reports and Literature Review.

Contrasting LRP5 Mutations in Osteoporosis-Pseudoglioma Syndrome and Osteopetrosis: Case Reports and Literature Review. | 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 Research Article Contrasting LRP5 Mutations in Osteoporosis-Pseudoglioma Syndrome and Osteopetrosis: Case Reports and Literature Review. Jason Peijer Hsieh, Chia-Feng Yang, Jia-You Liou, Pin-Hsuan Wang, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5329332/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: This study explores the critical role of LRP5 gene mutations in bone metabolism by presenting two cases of rare inherited disorders with contrasting skeletal manifestations. The study aims to highlight the spectrum of LRP5-associated disorders through the analysis of these cases. Results The first case involves a male patient with osteoporosis-pseudoglioma syndrome (OPPG) who has compound heterozygous missense mutations in LRP5 (c.1385G > A and c.1589T > C), each inherited from a different parent. These mutations, previously linked only to exudative vitreoretinopathy and classified as variants of uncertain significance, are now reclassified as pathogenic for OPPG. Additionally, whole-exome sequencing identified an incidental pathogenic mutation (c.1066C > T) in the GLA gene, indicating comorbid Fabry disease, which is associated with an increased risk of osteopenia. The second case involves a female patient diagnosed with osteopetrosis, who carries a missense mutation (c.640G > A) in LRP5, exemplifying the opposite end of the bone density spectrum. Conclusions: This study underscores the diverse skeletal manifestations associated with LRP5 mutations and provides valuable insights into genotype-phenotype correlations. By comparing LRP5 mutations linked to osteosclerosis and OPPG, this research enhances the understanding of LRP5-associated disorders. Osteoporosis pseudoglioma syndrome Osteopetrosis Fabry disease LRP5 whole exome sequencing Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Introduction The low-density lipoprotein receptor-related protein 5 (LRP5) gene plays a crucial role in bone metabolism and ocular development [ 1 ]. LRP5 encodes a co-receptor that, along with Frizzled-4, forms a receptor complex in the Wnt signaling pathway, which regulates osteoblast generation and differentiation. Furthermore, normal LRP5/Frizzled-4 signaling has been shown to be essential for proper development of the retinal vasculature. Genetic alterations in LRP5 have been associated with diverse phenotypes, primarily affecting skeletal and ocular structures, highlighting its importance in both bone and eye health [ 2 – 4 ]. Loss-of-function mutations in LRP5 are the primary cause of osteoporosis-pseudoglioma syndrome (OPPG), a rare autosomal recessive disorder characterized by severe osteoporosis and early-onset blindness [ 1 ]. OPPG has an estimated incidence of one in 2 million children in the United States [ 5 ]. Affected individuals typically present with congenital or infancy-onset vision loss due to abnormal retinal vasculature development [ 1 , 5 – 6 ]. The skeletal phenotype includes decreased bone mineral density (BMD), multiple fractures, bone fragility, long bone bowing, scoliosis, and sarcopenia [ 6 – 8 ]. Conversely, gain-of-function mutations in LRP5 have been identified as the genetic basis for high bone mass (LRP5-HBM) syndrome. This condition, inherited in an autosomal dominant pattern, results in osteosclerosis and significantly increased BMD [ 9 , 10 ]. Heterozygous carriers of loss-of-function LRP5 mutations, while not exhibiting the full OPPG phenotype, are at increased risk for moderately low bone mass. Additionally, these carriers have been found to have an elevated risk of developing exudative vitreoretinopathy, further emphasizing the gene's pleiotropic effects on both skeletal and ocular tissues [ 11 – 14 ]. The diverse phenotypes associated with LRP5 mutations underscore the complexity of Wnt signaling in bone and eye development. Understanding these genotype-phenotype correlations and underlying mechanisms is crucial for improving the diagnosis, management, and potential therapeutic interventions for individuals affected by LRP5-related disorders. Interestingly, our study also touches upon Fabry disease (FD; MIM 301500), an X-linked lysosomal storage disorder caused by deficient alpha-galactosidase A (α-Gal A) activity. FD affects approximately 1 in 40,000–60,000 males in the general population [ 15 ], leading to the accumulation of glycosphingolipids, primarily globotriaosylceramide (Gb3), in various tissues. Symptoms range from acroparesthesia, angiokeratoma, and hypohidrosis in childhood or adolescence to renal insufficiency, cardiomyopathy, and cerebrovascular disease in adulthood [ 16 – 20 ]. Recently, later-onset phenotypes of FD have been recognized, characterized by higher residual enzyme activity and milder or isolated symptoms [ 21 – 24 ]. Notably, recent reports indicate that patients with Fabry disease are at high risk for developing osteopenia [ 25 ]. In this report, we present two contrasting cases: a male patient with both OPPG and Fabry disease, and a female patient with osteopetrosis. The co-occurrence of OPPG and Fabry disease in one patient presents unique diagnostic and management challenges. Concurrently, the contrasting skeletal manifestations in these two patients, carrying missense mutations of the LRP5 gene in autosomal dominant (osteopetrosis) and autosomal recessive (OPPG) patterns, exemplify the complex effects of LRP5 mutations. In this study, we provide a comprehensive review and analysis of all reported LRP5 mutations, comparing gain-of-function variants causing osteosclerosis with loss-of-function variants resulting in OPPG. This analysis provides valuable insights into genotype-phenotype correlations and the spectrum of LRP5-associated disorders. Method Patient data Case No. 1 This is a 28-year-old male patient (height: 155.5 cm, weight: 48.5 kg) who presented with wheelchair dependency, right lower limb deformity and disability, and blindness. (Fig. 1 A) His orthopedic history began at age 2 with hip deformity, progressing to bilateral femur coxa vara and limping gait. At age 6, he underwent open reduction and internal fixation (ORIF) for a right proximal femur stress fracture, followed by multiple surgeries due to recurrent fractures and deformities in subsequent years. By age 12, DEXA examination revealed severe osteoporosis with a lumbar spine T-score of -4.9. The patient's visual impairment was first suspected in early infancy, with visual acuity measured at 20/200 bilaterally at age 3. Total blindness occurred in the left eye at age 12 and in the right eye by age 21. At presentation, physical examination showed right thigh deformity, muscle atrophy, and multiple surgical scars. X-rays revealed right femoral shaft fracture, bilateral bowing of femur and tibia, coxa vara, leg length discrepancy, and osteoporotic changes.(Fig. 1 B, 2 A) Scoliosis was noted with a T6-T12 Cobb angle of 83.7 degrees. (Fig. 2 B) Bone mineral density (BMD) with dual-energy X-ray absorptiometry (DEXA) examination of the lumbar spine showed a T-score of -5.2. Whole exome sequencing (WES) revealed compound heterozygous missense mutations in the LRP5 gene (c.1385G > A and c.1589T > C), associated with Osteoporosis-pseudoglioma syndrome (OPPG). Additionally, WES incidentally identified a pathogenic mutation (c.1066C > T) in the GLA gene, which is known to cause Fabry disease. Treatment involved 4 months of Teriparatide before surgery, which was discontinued due to economic constraints. After using Teriparatide for 4 months, along with vitamin D and calcium replacement, his DEXA T-score increased from − 5.2 to -4.9. The patient underwent ORIF for right femoral shaft fracture-nonunion. Post-operative rehabilitation progressed from non-weight-bearing to full weight-bearing over 5 months, with the patient achieving independent walking by 11 months post-surgery. Teriparatide was restarted for 4 months postoperatively, alongside continuous vitamin D and calcium supplementation. Bisphosphonates were initially withheld due to concerns about fracture nonunion and the concurrent use of Teriparatide. Follow-up X-rays confirmed bone union, and the patient's mobility significantly improved, although a residual leg length discrepancy necessitated a 6-cm shoe lift. Conservative treatment was maintained for asymptomatic coxa vara and scoliosis. Regarding Fabry disease, further biochemical analysis confirmed this diagnosis. The patient's plasma α-galactosidase A (GLA) enzyme activity was significantly reduced at 3.88 nmole/hr/mL (reference range: 5.41–17.99 nmole/hr/mL). Elevated levels of plasma globotriaosylsphingosine (lyso-Gb3) and globotriaosylceramide (Gb3) were observed, measuring 7.2 nM (reference: <2.6 nM) and 12.1 µg/mL (reference: <5.7 µg/mL), respectively. Notably, significant microalbuminuria was detected, with a microalbumin/creatinine ratio of 0.201 (reference: <0.03), indicating renal impairment consistent with Fabry disease. Based on these findings, enzyme replacement therapy for Fabry disease was initiated following diagnosis. Case No.2 A 59-year-old female with a known diagnosis of autosomal dominant osteopetrosis presented with a history of cervical myelopathy, chronic pain, and major depressive disorder. The patient's condition was initially identified at age 20 during a routine company health examination, which revealed abnormally high bone density. Between the ages of 30 and 40, she developed progressive headaches and diffuse bone pain, leading to further investigation and confirmation of osteopetrosis. At age 53, she underwent a C3-6 total laminectomy and right T1 hemilaminectomy to relieve spinal compression. The patient’s chronic pain has been managed with a combination of non-steroidal anti-inflammatory drugs (NSAIDs) and narcotic analgesics, including a fentanyl patch and oxycodone. Adjunctive treatments have included gabapentin and tramadol. Unfortunately, prolonged NSAID use has been associated with the development of chronic kidney disease, further complicating her management. The patient's psychiatric history is significant for major depressive disorder, with documented suicide attempts at ages 54 and 57. Her current psychiatric management includes venlafaxine and mirtazapine. Physical examination revealed characteristic features of osteopetrosis, including bony protrusions of the forehead, torus palatinus, square-shaped and enlarged mandible. (Fig. 3 ) Radiographic studies confirmed the osteopetrosis diagnosis: skull X-rays demonstrated diffusely thickened skull and spine, while long bone X-ray series showed sclerotic changes with thickened cortical bone without alterations in external shape. (Fig. 4 ) Family history is notable for osteopetrosis, as the patient's father and two younger brothers reportedly experienced similar symptoms (Fig. 5 ). Her father passed away during the patient's childhood due to unknown causes. Both younger brothers are deceased, having died by suicide, reportedly due to the intolerable pain associated with this disease. Whole exome sequencing (WES) revealed a missense mutation (c.640G > A, Ala214Try) in the LRP5 gene, consistent with the diagnosis of autosomal dominant osteopetrosis. Whole Exome Sequencing (WES) Analysis Following comprehensive collection of the patient's medical records, family history, and clinical presentations, and after obtaining informed consent and institutional review board approval, a blood sample was collected for genetic analysis. WES was performed on the patient sample following manufacturer-recommended protocols. Genomic DNA was fragmented to an average size of 180–280 base pairs (bp). Library preparation and target enrichment were conducted using the Illumina platform-compatible Roche KAPA HyperExome kit. Enriched DNA fragments were amplified and sequenced using a 2 x 150 bp Paired-End format on an Illumina NovaSeq platform. Bioinformatics analysis began with sequence alignment using BWA v0.7.17 software, followed by variant calling using GATK v4.1.2.0. Variants were annotated using the MedVar v3.1 database. Variant analysis was performed using Magic Bison ( https://magicbison.daopin-inc.com ), a web-based application developed by Daopin Incorporation. The analytical framework incorporated several principles. Candidate genes were identified based on the patient's phenotypic features using the Human Phenotype Ontology (HPO) and Gene Curation Coalition (GenCC) databases. Variants classified as benign or likely benign in the ClinVar database, or with prevalence exceeding 5% in Common Variation Databases (gnomAD, Allele Frequency Aggregator (ALFA) project, and Taiwan Biobank), were excluded. Genetic variants within the coding sequence (CDS) region were evaluated for potential impacts on protein structure using in silico prediction tools including SIFT, and PROVEAN. Identified variants were clinically interpreted according to the ACMG/AMP 2015 guidelines. Furthermore, variants unrelated to the patient's phenotypic features (not in candidate genes) but reported as pathogenic or likely pathogenic, or with potentially severe consequences (e.g., frameshift or nonsense mutations), and consistent with their inheritance pattern, were displayed in the "Proactive" column of Magic Bison. Literatures review and analysis of LRP5 mutations We conducted a comprehensive literature review of LRP5 gene mutations using PubMed to identify all reported LRP5 mutations in peer-reviewed publications. Additionally, we extracted all genetic mutation sites from the Human Gene Mutation Database (HGMD). The data collected from these two sources were integrated and subjected to thorough analysis. Each gene mutation was analyzed and classified according to its associated disease phenotype. Particular emphasis was placed on gene mutations linked to osteoporosis-pseudoglioma syndrome and osteopetrosis. For these disease-causing mutations, we performed in-depth analyses to elucidate why mutations in the same gene can result in contrasting clinical manifestations (osteoporosis versus osteopetrosis). Our aim was to gain insights into the underlying pathogenic mechanisms of these mutations. Results In case No.1, whole exome sequencing (WES) analysis revealed two variant alleles in the LRP5 gene. The first variant is a missense mutation, c.1385G > A (p.Arg462Gln), located in exon 6 of LRP5. This variant has been previously identified in a patient with familial exudative vitreoretinopathy (FEVR) and is currently classified as a variant of uncertain significance (VUS) [ 26 ]. The second variant is also a missense mutation, c.1589T > C (p.Ile530Thr), situated in exon 8 of LRP5. This variant was first submitted to ClinVar in 2022, associated with clinical presentations of familial exudative vitreoretinopathy. It is also currently classified as a variant of uncertain significance in ClinVar. The c.1385G > A mutation results in the substitution of arginine with glutamine. This change could significantly affect the protein's charge properties, potentially disrupting the formation of ionic bonds. In silico analysis supports the hypothesis that this missense variant has a deleterious effect on protein structure and function. According to the gnomAD dataset, the allele frequency of this variant in Asian populations is as rare as 0.0000116. The c.1589T > C mutation results in the substitution of a hydrophobic isoleucine with a hydrophilic threonine, potentially impacting the structural stability and interactions of the protein. In silico analysis suggests this missense variant has a deleterious effect on protein structure and function. The worldwide allele frequency of this variant is 0.000000684 according to the gnomAD dataset, indicating its rarity. Sanger sequencing of the LRP5 gene was conducted on the patient and his parents. The results showed that the patient inherited the c.1589T > C (p.Ile530Thr) variant from the mother, while the c.1385G > A (p.Arg462Gln) variant was inherited from the father (Fig. 6 A). Family pedigrees of the patient were shown in Fig. 6 B. Alignment of homologous sequences revealed that the affected amino acids in both variants are highly conserved across different species (Fig. 7 ). Based on these findings, we strongly suggest that these two mutations are pathogenic loss-of-function variants in the LRP5 gene, contributing to the development of osteoporosis-pseudoglioma syndrome (OPPG). Through proactive analysis, we discovered that the patient carries a pathogenic mutation in the GLA gene (c.1066C > T, p.Arg356Trp), associated with the renal variant of Fabry disease. To confirm this finding, Sanger sequencing of the GLA gene was performed on the patient and his mother. The results revealed that the patient inherited this GLA gene mutation from his mother's side. Subsequent family studies identified several family members who also carry this mutation (Fig. 5 ). Notably, these individuals were found to have renal impairment consistent with Fabry disease. This incidental finding demonstrates the capacity of comprehensive WGS analysis to uncover clinically relevant genetic variants beyond the primary diagnostic focus, potentially impacting both patient care and familial genetic counseling In case No.2, whole exome sequencing (WES) revealed a heterozygous missense mutation (c.640G > A; p.A214T) in exon 3 of the LRP5 gene. This specific mutation has previously been reported to cause the high-bone-mass phenotype [ 27 ]. The presence of this known pathogenic variant is consistent with the clinical diagnosis of autosomal dominant osteopetrosis. Based on our comprehensive literature review and analysis of LRP5 mutations, a total of 469 mutation sites in the LRP5 gene have been reported to date. These mutations include 326 missense mutations, 35 nonsense mutations, 32 splicing mutations, 1 regulatory mutation, 41 small deletions, 25 small insertions/duplications, 2 indel mutations, 6 gross deletions, and 1 repeat variation. The most commonly reported mutations in the LRP5 gene are associated with Familial Exudative Vitreoretinopathy (FEVR), with 274 mutations linked to this condition. These mutations are highly suspected to result in loss of function. However, FEVR can also be caused by defects in other genes and conditions [ 28 ]. Furthermore, LRP5-associated FEVR is inherited in an autosomal dominant pattern with incomplete penetrance [ 29 ]. These factors make it difficult to definitively establish the pathogenicity of many of these mutations. Consequently, they are often classified as variants of uncertain significance, similar to the two mutations identified in our study. Given this uncertainty, we have chosen to exclude FEVR-related mutations from our primary mutation characteristics analysis. This decision allows us to focus on mutations with more clearly established pathogenicity and phenotypic correlations, particularly those associated with bone density disorders such as osteoporosis-pseudoglioma syndrome and osteopetrosis/high bone mass trait. In our analysis, mutations associated with osteoporosis-pseudoglioma syndrome (OPPG) were identified at 88 distinct sites. These included 59 point mutations, comprising 41 missense mutations and 18 nonsense mutations. Additionally, we identified 8 splicing mutations, 10 small deletions, 5 small duplications, 4 gross deletions, and 2 small indels. All of these mutations are classified as loss-of-function mutations. Based on the severe phenotype observed in our OPPG patient, the two missense mutations identified (c.1385G > A, p.R462Q; c.1589T > C, p.I560T) are suggested to cause a significant loss of LRP5 function. Because nonsense, frameshift, and splicing mutations are readily understood as loss-of-function mutations, our analysis of loss-of-function mutations specifically focused on missense mutations, as well as in-frame insertion or deletion mutations. There was a total of 42 such mutations, including 41 missense mutations and one in-frame deletion mutation. These mutations are detailed in Fig. 8 . In contrast, mutations associated with osteopetrosis, osteosclerosis, and high bone mass traits were identified at 20 distinct mutations, the majority of which were missense mutations (18 out of 20). Notably, no nonsense mutations were observed in this group. Interestingly, one insertion mutation (c.509_514dupGGGGTG, p.G171_E172insGG) and one deletion mutation (c.511_516delGGTGAG, p.G171_E172del) were associated with gain-of-function effects. Both mutations are in-frame, suggesting that the LRP5 protein may retain functional integrity despite these alterations. Nearly all gain-of-function mutations were located in exons 2–4, with only two mutations (c.4240C > A, p.R1414S and c.4574T > C, p.V1525A) identified in exon 20 and 22 of the LRP5 gene (Fig. 7 ). The most frequently occurring mutations were c.724G > A, c.512G > T, and c.758C > T, with no significant differences in ethnic distribution. Additionally, mutations in exon 3 appeared to be associated with more severe phenotypes. The mutation c.640G > A (p. A214T) identified in our patient is also located in exon 3 of the LRP5 gene, and her severe phenotype is consistent with this observed trend. Discussion The LRP5 gene plays a critical role in bone metabolism by participating in the Wnt-β-catenin signaling pathway. It encodes a transmembrane co-receptor, LRP5, which partners with the Frizzled receptor to bind Wnt ligands and initiate signaling. This interaction leads to the sequestration of the cytoplasmic destruction complex by the LRP5-Frizzled receptor complex. The destruction complex, which includes proteins such as Axin, APC (adenomatous polyposis coli), GSK-3β (glycogen synthase kinase 3 beta), and CK1 (casein kinase 1), normally regulates β-catenin levels by targeting it for degradation. In the absence of Wnt signaling, the destruction complex facilitates β-catenin's phosphorylation, leading to its ubiquitination and proteasomal degradation, preventing its accumulation (Fig. 9 A). However, when Wnt ligands bind to the LRP5-Frizzled receptor complex, the destruction complex is sequestered, allowing β-catenin to escape degradation. The accumulated β-catenin then translocates to the nucleus, where it interacts with T-cell factor (TCF)/ lymphoid enhancer factor (LEF) transcription factors to modulate gene expression, promoting bone formation (Fig. 9 B). In LRP5 loss-of-function mutations, such as in osteoporosis-pseudoglioma syndrome, the lack of functional LRP5 lead Wnt cannot bind LRP5-Frizzled complex result in destruction complex is not appropriately sequestered, leading to continuous β-catenin degradation by destruction complex. This reduces β-catenin levels in the nucleus, decreasing Wnt target gene transcription and impairing bone formation. (Fig. 9 C) Conversely, in LRP5 gain-of-function mutations (as seen in Osteopetrosis or high bone mass phenotypes), Wnt signaling is abnormally enhanced by specific mechanisms of the mutated LRP5. This leads to the inhibition of the destruction complex, preventing the phosphorylation and degradation of β-catenin. As a result, β-catenin accumulates in the cytoplasm and translocates to the nucleus, where it activates the transcription of Wnt target genes, promoting excessive bone formation through increased osteoblast activity and elevated bone density (Fig. 9 D, 9 E). It is noteworthy that most gain-of-function mutations are concentrated in exons 2–4 of the LRP5 gene, with two additional mutations located in exon 20 and 22. This distribution contrasts with that of loss-of-function mutations, which are more widely dispersed throughout the LRP5 gene. This suggests that gain-of-function mutations may occur at specific sites within the LRP5 protein, conferring unique properties that enhance its activity. In the regulation of the Wnt signaling pathway, DKK-1 (Dickkopf-1) and SOST (Sclerostin) plays critical roles as inhibitors of bone formation. They function by disrupting the interaction between Wnt ligands and the LRP5 co-receptor, effectively blocking the canonical Wnt pathway. The exons 2–4 of LRP5 encode the first β-propeller region of the protein's extracellular domain, which serves as the primary binding site for SOST and concurrently influences the interaction of DKK-1 with the third β-propeller region.[ 30 ] These domains are crucial as they form the primary binding sites for SOST. Previous studies have demonstrated that specific amino acid substitutions within these domains of LRP5 can significantly alter its interaction with SOST. Mutations such as D111Y, G171R, A214T, A242T, T253I, and M282V have been shown to reduce the affinity of LRP5 for SOST, thereby facilitating Wnt binding to LRP5 and activating the canonical Wnt pathway, leading to increased bone formation. [ 31 ] In our study, Patient 2 was found to have a c.640G > A (p.A214T) mutation located in exon 3, which results in the substitution of the conserved 214th amino acid in 1st β-propeller domains of LRP5 from alanine to threonine. This mutation is believed to weaken the binding of LRP5 to SOST, thereby enhancing Wnt signaling and promoting bone formation. Two gain-of-function mutations located in exons 20 and 22 of the LRP5 gene are believed to induce alterations of the function in the cytoplasmic domain of the receptor protein, which contains five highly conserved PPP-SPxS motifs. Phosphorylation of these motifs is essential for forming the binding site for Axin, a critical component of the destruction complex [ 32 ]. Studies have shown that the c.4574T > C (p.V1525A) mutation enhances the binding of LRP5 to Axin, resulting in the sequestration of the destruction complex. This process allows β-catenin to accumulate, thereby promoting bone formation [ 33 ]. The treatment strategies for Osteoporosis-Pseudoglioma Syndrome (OPPG) primarily focus on symptom management and the prevention of complications, as there is currently no cure for the condition. Bisphosphonate therapy is commonly used in OPPG to inhibit bone resorption and slow down bone loss, with substantial evidence supporting its safety and efficacy in managing the condition [ 34 , 35 ]. Additionally, calcium and vitamin D supplementation are recommended to maintain bone health and enhance the effectiveness of bisphosphonate therapy. Physical therapy and rehabilitation play a crucial role in improving muscle strength and coordination, helping to prevent falls and manage the physical challenges associated with OPPG. Orthopedic interventions are often considered to treat fractures or correct bone deformities that frequently occur in individuals with OPPG. It is important that treatment plans are personalized based on the patient’s age, symptom severity, and overall health status, with regular monitoring of bone density and careful management of physical activity being critical aspects of long-term care. LRP5-related osteopetrosis typically presents a milder clinical course compared to other forms of osteopetrosis [ 36 , 37 ]. However, severe complications can still arise in certain cases, as observed in patient 2 of our cohort. Currently, there are no effective treatments specifically targeting this form of osteopetrosis. LHRH analogues have been explored with the rationale of potentially reducing bone formation by influencing sex hormone levels [ 38 ]; however, this approach requires further research to determine its efficacy. As a result, management often centers on monitoring and addressing symptoms as they arise rather than attempting to modify the underlying increased bone density. Treatment plans should be tailored to each patient's specific presentation and symptoms. Symptomatic management, including pain control, should be implemented as necessary. However, caution must be exercised when prescribing analgesics due to their addictive or dependent potential. Additionally, the use of nonsteroidal anti-inflammatory drugs (NSAIDs) should be carefully monitored due to the risk of renal impairment, especially in patients with compromised kidney function. Regular follow-up evaluations, with particular attention to potential neurological complications such as cranial nerve and spinal cord compression, are crucial components of ongoing care. In cases of neurologic compression, timely surgical intervention may be required. This approach underscores the importance of a multidisciplinary care team in managing LRP5-related osteopetrosis, given the current limitations in targeted therapeutic options and the potential for diverse complications. The incidental identification of a pathogenic GLA mutation associated with Fabry disease in Patient No. 1 through whole exome sequencing (WES) raises important questions about the potential interplay between Fabry disease and Osteoporosis-Pseudoglioma Syndrome (OPPG). Given the known association between Fabry disease and osteopenia [ 25 , 39 ], it is reasonable to consider whether Fabry disease might exacerbate bone issues in patients with Osteogenesis Imperfecta (OPPG). Notably, Case 1 demonstrated frequent fractures and bone deformities that were somewhat more severe than those typically reported in OPPG cases. It remains unclear whether this increased severity is due to the combined effects of Fabry disease or if it results from delayed and inadequate treatment owing to a late diagnosis. This observation highlights the need for further research into the potential synergistic effects of these rare disorders. This case highlights the value of comprehensive genetic analysis in clinical practice. The incidentally discovery of Fabry disease through WES not only provides insights into the patient's complex phenotype but also offers significant benefits for the patient's family. By conducting a thorough family tree study, it may be possible to identify other family members with Fabry disease, allowing for early intervention with enzyme replacement therapy (ERT) before the onset of irreversible complications such as renal failure. The utilization of WES or whole genome sequencing (WGS) in this context exemplifies the power of precision medicine. These advanced genetic tools can not only elucidate the genetic basis of clinically apparent conditions but also unveil latent genetic disorders that may have profound implications for patients and their families. The early detection of such conditions can directly benefit individuals by enabling timely interventions and personalized management strategies. Conclusion This study underscores the critical role of LRP5 in bone metabolism, as demonstrated by two contrasting cases of LRP5 mutations leading to Osteoporosis-Pseudoglioma Syndrome (OPPG) and osteopetrosis. This report also highlights the importance of WES/WGS in diagnosing and managing complex skeletal disorders, revealing potential synergistic effects between Fabry disease and OPPG, and emphasizing the need for further research into genotype-phenotype correlations. The integration of precision medicine, through tools like WES/WGS, proves invaluable in uncovering latent genetic conditions, ultimately guiding more personalized and effective treatment strategies. Abbreviations BMD bone mineral density DKK-1 Dickkopf-1 FD Fabry disease FEVR familial exudative vitreoretinopathy LEF lymphoid enhancer factor OPPG oteoporosis-pseudoglioma syndrome SOST Sclerostin TCF T-cell factor WES Whole exome sequencing WGS Whole genome sequencing Declarations Acknowledgements Not applicable. Author contributions All authors contributed to the study conception and design, as well as its review and editing. JPH, YHL and JYL performed the systematic review and data collection. HJP, YHL and DMN were major contributors to the writing of the manuscript. CFY, PHW, CKF and CCW contributed to the oversight of the manuscript. All the authors have read and approved the final manuscript. Funding The study was supported by an industry-academia collaboration project between Taipei Veterans General Hospital and Daopin Incorporation [Grant No.: R2200201], as well as by the Ministry of Science and Technology, Taiwan [Grant No.: NSTC112-2634-F-A49-003-1]. Availability of data and materials Due to considerations of patient privacy and confidentiality, the datasets produced and examined in the present study are not publicly accessible. Anonymized data can be provided by the corresponding author upon reasonable request. Ethics approval and consent to participate All procedures involving human participants were conducted in accordance with the ethical standards of the Taipei Veterans General Hospital Institutional Review Board, which approved the study (2021-10-001CC). 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Mutation spectrum of the LRP5, NDP, and TSPAN12 genes in Chinese patients with familial exudative vitreoretinopathy. Investig Ophthalmol Vis Sci. 2017;58(13):5949–57. Meikle PJ, et al. Prevalence of lysosomal storage disorders. JAMA. 1999;281(3):249–54. Desnick RJ, Wasserstein MP. Fabry disease: clinical features and recent advances in enzyme replacement therapy. Adv Nephrol Necker Hosp. 2001;31:317–39. Desnick RJ, Brady RO. Fabry disease in childhood. J Pediatr. 2004;144(5 Suppl):S20–6. Bhatia GS, et al. Severe left ventricular hypertrophy in Anderson-Fabry disease. Heart. 2004;90(10):1136. Zarate YA, Hopkin RJ. Fabry's disease. Lancet. 2008;372(9647):1427–35. Weidemann F, et al. Cardiac challenges in patients with Fabry disease. Int J Cardiol. 2010;141(1):3–10. Nakao S, et al. An atypical variant of Fabry's disease in men with left ventricular hypertrophy. N Engl J Med. 1995;333(5):288–93. Kotanko P, et al. Results of a nationwide screening for Anderson-Fabry disease among dialysis patients. J Am Soc Nephrol. 2004;15(5):1323–9. Tanaka N, et al. Recurrent strokes in a young adult patient with Fabry's disease. Eur J Neurol. 2005;12(6):486–7. Smid BE, van der Tol L, Biegstraaten M, Linthorst GE, Hollak CE, Poorthuis BJ. Plasma globotriaosylsphingosine in relation to phenotypes of Fabry disease. J Med Genet. 2015;52:262–8. Mersebach H, Johansson J-O, Rasmussen åsekrogh. Bengt-Åke Bengtsson, Kirsten Rosenberg, Lis Hasholt, Sven Asger Sørensen, Søren schwartz Sørensen & Ulla Feldt-Rasmussen. Osteopenia: a common aspect of Fabry disease. Predictors of bone mineral density. Genet Med. 2007;9(12):812–8. Tao T, Xu N, Li J, Li H, Qu J, Yin H, Liang J, Zhao M. Xiaoxin Li, and Lvzhen Huang. Ocular Features and Mutation Spectrum of Patients With Familial Exudative Vitreoretinopathy. Invest Ophthalmol Vis Sci. 2021;62(15):4. Van Wesenbeeck L, Cleiren E, Gram J, Beals RK, Bénichou O, Scopelliti D, Key L, Renton T, Bartels C, Gong Y, Warman ML, De Vernejoul MC, Bollerslev J, Van Hul W. Six novel missense mutations in the LDL receptor-related protein 5 (LRP5) gene in different conditions with an increased bone density. Am J Hum Genet. 2003;72(3):763–71. Hiroyuki Kondo. Complex genetics of familial exudative vitreoretinopathy and related pediatric retinal detachments. Taiwan J Ophthalmol. 2015;5(2):56–62. Luo J, Li J, Zhang X, Li JK, Chen HJ, Zhao PQ, Fei P. Five novel copy number variations detected in patients with familial exudative vitreoretinopathy. Mol Vis. 2021;27:632–42. Zhao D, Sun L, Jing WZ, Wang HBZO, Jiang Y, Xia W. Xiaoping Xing, and Mei Li. Novel mutation in LRP5 gene cause rare osteosclerosis: cases studies and literature review. Mol Genet Genomics. 2023;298(3):683–92. Ai M, Heeger S, Bartels CF, Schelling DK. Osteoporosis-Pseudoglioma Collaborative Group Clinical and molecular findings in osteoporosis-pseudoglioma syndrome. Am J Hum Genet. 2005;77:741–53. Haÿ E, Buczkowski T, Marty C, et al. Peptide-based mediated disruption of N-cadherin-LRP5/6 interaction promotes Wnt signaling and bone formation. J Bone Min Res. 2012;27(9):1852–63. Guo J, Cooper LF. Influence of an LRP5 cytoplasmic SNP on Wnt signaling and osteoblastic differentiation. Bone. 2007;40(1):57–67. Streeten EA, McBride D, Puffenberger E, Hoffman ME, Pollin TI, Donnelly P, Sack P, Morton H. Osteoporosis-pseudoglioma syndrome: description of 9 new cases and beneficial response to bisphosphonates. Bone. 2008;43(3):584–90. Iordanis Papadopoulos E, Bountouvi A, Attilakos E, Gole A, Dinopoulos M, Peppa. Polyxeni Nikolaidou & Anna Papadopoulou. Osteoporosis-pseudoglioma syndrome: clinical, genetic, and treatment-response study of 10 new cases in Greece. Eur J Pediatr. 2019;178(3):323–9. Khan MA, Ullah A, Naeem M. Whole exome sequencing identified two novel homozygous missense variants in the same codon of CLCN7 underlying autosomal recessive infantile malignant osteopetrosis in a Pakistani family. Mol Biol Rep. 2018;45(4):565–70. El-Kamah GY, Mehrez MI, Taher MB, El-Bassyouni HT, Gaber KR, Amr KS. Outlining the Clinical Profile of TCIRG1 14 Variants including 5 Novels with Overview of ARO Phenotype and Ethnic Impact in 20 Egyptian Families. Genes (Basel). 2023;14(4):900. Jafri SM, Burke EA, Adams DR, Evans C, Bulas D, Weinerman SA, Pan K, Collins MT, Markello TC, Vezina G, Gahl WA, Toro C. Potential therapeutic response in a severe case of autosomal dominant osteopetrosis type I. J Transl Genet Genom. 2022;6:281–9. Germain DP. Osteopenia and osteoporosis: previously unrecognized manifestations of Fabry disease. Clin Genet. 2005;68:93–5. Cite Share Download PDF Status: Posted Version 1 posted 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-5329332","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":377770947,"identity":"7399921f-ddc8-4697-b487-03dc71ca1da6","order_by":0,"name":"Jason Peijer Hsieh","email":"","orcid":"","institution":"Taipei Veterans General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jason","middleName":"Peijer","lastName":"Hsieh","suffix":""},{"id":377770948,"identity":"a208bdf3-13d8-4f4f-83eb-0e24ada28053","order_by":1,"name":"Chia-Feng Yang","email":"","orcid":"","institution":"Taipei Veterans General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Chia-Feng","middleName":"","lastName":"Yang","suffix":""},{"id":377770949,"identity":"4e8ab943-0318-41db-93df-55bba65c91ba","order_by":2,"name":"Jia-You Liou","email":"","orcid":"","institution":"Taipei Veterans General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jia-You","middleName":"","lastName":"Liou","suffix":""},{"id":377770950,"identity":"50b02801-74c5-4162-b78b-69fdba368bb2","order_by":3,"name":"Pin-Hsuan Wang","email":"","orcid":"","institution":"Taipei Veterans General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Pin-Hsuan","middleName":"","lastName":"Wang","suffix":""},{"id":377770951,"identity":"e52ceaf4-a89a-4814-9493-1397035ae6d6","order_by":4,"name":"Chi-Kuang Feng","email":"","orcid":"","institution":"Taipei Veterans General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Chi-Kuang","middleName":"","lastName":"Feng","suffix":""},{"id":377770952,"identity":"32d4db24-bb29-4bba-8665-e9aeaff29aeb","order_by":5,"name":"Chang-Chi Weng","email":"","orcid":"","institution":"Taipei Veterans General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Chang-Chi","middleName":"","lastName":"Weng","suffix":""},{"id":377770953,"identity":"f8f30ee7-f16c-4e32-929f-ae0ceb5e4677","order_by":6,"name":"Yung-Hsiu Lu","email":"","orcid":"","institution":"Taipei Veterans General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yung-Hsiu","middleName":"","lastName":"Lu","suffix":""},{"id":377770954,"identity":"5e92a837-50fc-436b-91a5-cc4fa01ddccc","order_by":7,"name":"Dau-Ming Niu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA0klEQVRIiWNgGAWjYDCCAyBkIMHDxt7AwEyClgILGT6eA0haDhDQwsDwocJGTiKBSC18184ePMwDcpjkG8PPBRU2DPzt3QnMH9twa5G8nZcA0SKdYyw940wag8SZsxsYDuLRYnA7xwCmxUCat+0wMChygVq2EaNF8ozxbxK1SPCYEWeLJFDLwTkgLTxpZdY8Z9J4QH45cPYfbi18t3OMP7z5U2cv3354820eYGDzt/dufFBxBrcWJMBhACJ5QMQBojQwMLA/IFLhKBgFo2AUjDQAANUYTu052WJNAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0003-3962-1739","institution":"Taipei Veterans General Hospital","correspondingAuthor":true,"prefix":"","firstName":"Dau-Ming","middleName":"","lastName":"Niu","suffix":""}],"badges":[],"createdAt":"2024-10-25 03:55:07","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5329332/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5329332/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":71925136,"identity":"1eb3812d-d1b8-4cdf-8509-be386e0164a7","added_by":"auto","created_at":"2024-12-19 18:32:34","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":309844,"visible":true,"origin":"","legend":"\u003cp\u003eClinical presentation of the case 1 patient. (A) Photograph demonstrating the patient's wheelchair dependency and bilateral blindness. (B) X-ray radiograph showing a peri-implant fracture of the right femur.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-5329332/v1/237f3efc2df0602fa058f006.png"},{"id":71925131,"identity":"3b9564a1-48e1-4c2c-8761-ca5a8a629fad","added_by":"auto","created_at":"2024-12-19 18:32:34","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":211744,"visible":true,"origin":"","legend":"\u003cp\u003eRadiographic Findings in Patient 1. (A) X-ray demonstrating bilateral bowing of the femur and tibia, coxa vara, and a leg length discrepancy. (B) X-ray showing severe scoliosis at the time of presentation.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-5329332/v1/cb83a86dfb5d20a3e589745f.png"},{"id":71925700,"identity":"8343b65d-401e-4b34-bb46-f1b53dfe5a4f","added_by":"auto","created_at":"2024-12-19 18:40:34","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":468730,"visible":true,"origin":"","legend":"\u003cp\u003eClinical Examination of Patient 2. (A) Bony protrusions of the forehead and a square-shaped, enlarged mandible. (B) Presence of torus palatinus.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-5329332/v1/4e8b4c18206f6aabdb99be8f.png"},{"id":71925972,"identity":"9f0c6098-ff7d-4d63-8467-ce97ace2d4f6","added_by":"auto","created_at":"2024-12-19 18:48:34","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":228362,"visible":true,"origin":"","legend":"\u003cp\u003eX-rays Showing Bone Abnormalities. (A) Diffusely thickened skull. (B) Long bone with sclerotic changes. Note the thickened cortical bone without changes to the external shape of the bone.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-5329332/v1/bd346e4637bc4d243c42694e.png"},{"id":71925701,"identity":"a5690501-80a5-4be4-8e20-a3ae648fa3f1","added_by":"auto","created_at":"2024-12-19 18:40:34","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":33358,"visible":true,"origin":"","legend":"\u003cp\u003eCase 2 Family Pedigree. The filled symbol indicates the affected individual, and the arrow points to Case 2 (proband).\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-5329332/v1/0ec7df06b1cbbea94b3fb323.png"},{"id":71925704,"identity":"a826eb76-c6e1-48be-b7cb-f9ab3a896dae","added_by":"auto","created_at":"2024-12-19 18:40:34","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":208346,"visible":true,"origin":"","legend":"\u003cp\u003eGenetic analysis of the proband and family members. (A) Sanger sequencing chromatograms showing the identified mutations in the LRP5 and GLA genes for the proband and their parents. (B) Family pedigree diagram illustrating the distribution of genetic variants among family members. The proband is marked by an arrow. Symbols are filled as follows: black for individuals carrying the LRP5 c.1385G\u0026gt;A variant; diagonal lines for those carrying the LRP5 c.1589T\u0026gt;C variant; and gray for carriers of the GLA c.1066C\u0026gt;T variant.\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-5329332/v1/baab03dbac4205b0a9ac24c3.png"},{"id":71925137,"identity":"0969f5cd-2914-41c0-9205-bafe446e505d","added_by":"auto","created_at":"2024-12-19 18:32:35","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":198467,"visible":true,"origin":"","legend":"\u003cp\u003eProtein conservation alignment across different species. The blue arrow represents the mutation site. Protein sequence alignments revealed that c.1385G\u0026gt;A and c.1589T\u0026gt;C in LRP5 gene were extremely evolutionarily conserved.\u003c/p\u003e","description":"","filename":"7.png","url":"https://assets-eu.researchsquare.com/files/rs-5329332/v1/148811f01c120d5ceca776d5.png"},{"id":71925702,"identity":"e0005dff-a8c2-4937-80f1-0c58555e3ec9","added_by":"auto","created_at":"2024-12-19 18:40:34","extension":"png","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":216961,"visible":true,"origin":"","legend":"\u003cp\u003eSchematic representation of LRP5 mutations, protein structure and domain organization associated with loss-of-function (TOP) and gain-of-function (Bottom). The mutation observed in the case study of this research are highlighted in red.\u003c/p\u003e","description":"","filename":"8.png","url":"https://assets-eu.researchsquare.com/files/rs-5329332/v1/38c4ac1746372ec856ae661c.png"},{"id":71925134,"identity":"d8919a0c-6cee-4586-81e1-87a8197de6dc","added_by":"auto","created_at":"2024-12-19 18:32:34","extension":"png","order_by":9,"title":"Figure 9","display":"","copyAsset":false,"role":"figure","size":194342,"visible":true,"origin":"","legend":"\u003cp\u003eSchematic illustration of the Wnt signaling pathway.\u003c/p\u003e\n\u003cp\u003e(A) During WNT pathway inactivation, DKK1 or SOST (antagonists of the WNT pathway) bind to the LRP5/6 co-receptors, preventing WNT from engaging with the LRP5/Frizzled receptor complex. As a result, the cytoplasmic destruction complex is not sequestered by the LRP5-Frizzled complex, allowing it to remain active. This leads to the degradation of β-catenin, reducing its nuclear levels. Consequently, the transcription of WNT target genes is decreased, which decrease osteoblast differentiation and function. (B) During WNT pathway activation, Wnt proteins bind to the LRP5/Frizzled receptor complex. This activated receptor complex sequesters the destruction complex, preventing the degradation of β-catenin. As a result, β-catenin accumulates in the cytoplasm and subsequently translocates to the nucleus, where it interacts with TCF/LEF transcription factors to activate WNT target genes. This process promotes osteoblast differentiation and stimulates bone formation. (C) In LRP5 loss-of-function mutations, the lack of functional LRP5 prevents the formation of the normal LRP5/Frizzled receptor complex, which typically sequesters the destruction complex. As a result, the destruction complex continuously degrades β-catenin, reducing its nuclear levels, decreasing WNT target gene transcription, and impairing bone formation. In LRP5 gain-of-function mutations, two possible mechanisms may lead to the accumulation of β-catenin and promote bone formation. (D) First, mutations located in exons 2–4 of the LRP5 gene are thought to reduce the affinity of LRP5 for SOST/DKK1. Without SOST/DKK1 inhibition, WNT can more easily bind to LRP5, activating the canonical WNT pathway and increasing bone formation. (E) Second, mutations in exons 20 and 22 are believed to enhance the binding of LRP5 to Axin, a key component of the destruction complex. This enhanced binding leads to the continuous sequestration of the destruction complex, even in the absence of WNT signaling. As a result, β-catenin accumulates, further promoting bone formation.\u003c/p\u003e","description":"","filename":"9.png","url":"https://assets-eu.researchsquare.com/files/rs-5329332/v1/50d8c8ca3eb43cdc06e38f16.png"},{"id":72431797,"identity":"63fbec93-dd79-446d-893a-2b9d12896945","added_by":"auto","created_at":"2024-12-27 04:18:28","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2989234,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5329332/v1/cdafeb13-5c6f-4ab6-9c86-2d33c59f1beb.pdf"}],"financialInterests":"","formattedTitle":"Contrasting LRP5 Mutations in Osteoporosis-Pseudoglioma Syndrome and Osteopetrosis: Case Reports and Literature Review.","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe low-density lipoprotein receptor-related protein 5 (LRP5) gene plays a crucial role in bone metabolism and ocular development [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. LRP5 encodes a co-receptor that, along with Frizzled-4, forms a receptor complex in the Wnt signaling pathway, which regulates osteoblast generation and differentiation. Furthermore, normal LRP5/Frizzled-4 signaling has been shown to be essential for proper development of the retinal vasculature. Genetic alterations in LRP5 have been associated with diverse phenotypes, primarily affecting skeletal and ocular structures, highlighting its importance in both bone and eye health [\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eLoss-of-function mutations in LRP5 are the primary cause of osteoporosis-pseudoglioma syndrome (OPPG), a rare autosomal recessive disorder characterized by severe osteoporosis and early-onset blindness [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. OPPG has an estimated incidence of one in 2\u0026nbsp;million children in the United States [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Affected individuals typically present with congenital or infancy-onset vision loss due to abnormal retinal vasculature development [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. The skeletal phenotype includes decreased bone mineral density (BMD), multiple fractures, bone fragility, long bone bowing, scoliosis, and sarcopenia [\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eConversely, gain-of-function mutations in LRP5 have been identified as the genetic basis for high bone mass (LRP5-HBM) syndrome. This condition, inherited in an autosomal dominant pattern, results in osteosclerosis and significantly increased BMD [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Heterozygous carriers of loss-of-function LRP5 mutations, while not exhibiting the full OPPG phenotype, are at increased risk for moderately low bone mass. Additionally, these carriers have been found to have an elevated risk of developing exudative vitreoretinopathy, further emphasizing the gene's pleiotropic effects on both skeletal and ocular tissues [\u003cspan additionalcitationids=\"CR12 CR13\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe diverse phenotypes associated with LRP5 mutations underscore the complexity of Wnt signaling in bone and eye development. Understanding these genotype-phenotype correlations and underlying mechanisms is crucial for improving the diagnosis, management, and potential therapeutic interventions for individuals affected by LRP5-related disorders.\u003c/p\u003e \u003cp\u003eInterestingly, our study also touches upon Fabry disease (FD; MIM 301500), an X-linked lysosomal storage disorder caused by deficient alpha-galactosidase A (α-Gal A) activity. FD affects approximately 1 in 40,000\u0026ndash;60,000 males in the general population [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], leading to the accumulation of glycosphingolipids, primarily globotriaosylceramide (Gb3), in various tissues. Symptoms range from acroparesthesia, angiokeratoma, and hypohidrosis in childhood or adolescence to renal insufficiency, cardiomyopathy, and cerebrovascular disease in adulthood [\u003cspan additionalcitationids=\"CR17 CR18 CR19\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Recently, later-onset phenotypes of FD have been recognized, characterized by higher residual enzyme activity and milder or isolated symptoms [\u003cspan additionalcitationids=\"CR22 CR23\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Notably, recent reports indicate that patients with Fabry disease are at high risk for developing osteopenia [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn this report, we present two contrasting cases: a male patient with both OPPG and Fabry disease, and a female patient with osteopetrosis. The co-occurrence of OPPG and Fabry disease in one patient presents unique diagnostic and management challenges. Concurrently, the contrasting skeletal manifestations in these two patients, carrying missense mutations of the LRP5 gene in autosomal dominant (osteopetrosis) and autosomal recessive (OPPG) patterns, exemplify the complex effects of LRP5 mutations.\u003c/p\u003e \u003cp\u003eIn this study, we provide a comprehensive review and analysis of all reported LRP5 mutations, comparing gain-of-function variants causing osteosclerosis with loss-of-function variants resulting in OPPG. This analysis provides valuable insights into genotype-phenotype correlations and the spectrum of LRP5-associated disorders.\u003c/p\u003e"},{"header":"Method","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatient data\u003c/h2\u003e \u003cdiv id=\"Sec4\" class=\"Section3\"\u003e \u003ch2\u003eCase No. 1\u003c/h2\u003e \u003cp\u003eThis is a 28-year-old male patient (height: 155.5 cm, weight: 48.5 kg) who presented with wheelchair dependency, right lower limb deformity and disability, and blindness. (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA) His orthopedic history began at age 2 with hip deformity, progressing to bilateral femur coxa vara and limping gait. At age 6, he underwent open reduction and internal fixation (ORIF) for a right proximal femur stress fracture, followed by multiple surgeries due to recurrent fractures and deformities in subsequent years. By age 12, DEXA examination revealed severe osteoporosis with a lumbar spine T-score of -4.9.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe patient's visual impairment was first suspected in early infancy, with visual acuity measured at 20/200 bilaterally at age 3. Total blindness occurred in the left eye at age 12 and in the right eye by age 21.\u003c/p\u003e \u003cp\u003eAt presentation, physical examination showed right thigh deformity, muscle atrophy, and multiple surgical scars. X-rays revealed right femoral shaft fracture, bilateral bowing of femur and tibia, coxa vara, leg length discrepancy, and osteoporotic changes.(Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB, \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA) Scoliosis was noted with a T6-T12 Cobb angle of 83.7 degrees. (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB) Bone mineral density (BMD) with dual-energy X-ray absorptiometry (DEXA) examination of the lumbar spine showed a T-score of -5.2. Whole exome sequencing (WES) revealed compound heterozygous missense mutations in the LRP5 gene (c.1385G\u0026thinsp;\u0026gt;\u0026thinsp;A and c.1589T\u0026thinsp;\u0026gt;\u0026thinsp;C), associated with Osteoporosis-pseudoglioma syndrome (OPPG). Additionally, WES incidentally identified a pathogenic mutation (c.1066C\u0026thinsp;\u0026gt;\u0026thinsp;T) in the GLA gene, which is known to cause Fabry disease.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eTreatment involved 4 months of Teriparatide before surgery, which was discontinued due to economic constraints. After using Teriparatide for 4 months, along with vitamin D and calcium replacement, his DEXA T-score increased from \u0026minus;\u0026thinsp;5.2 to -4.9.\u003c/p\u003e \u003cp\u003eThe patient underwent ORIF for right femoral shaft fracture-nonunion. Post-operative rehabilitation progressed from non-weight-bearing to full weight-bearing over 5 months, with the patient achieving independent walking by 11 months post-surgery. Teriparatide was restarted for 4 months postoperatively, alongside continuous vitamin D and calcium supplementation. Bisphosphonates were initially withheld due to concerns about fracture nonunion and the concurrent use of Teriparatide. Follow-up X-rays confirmed bone union, and the patient's mobility significantly improved, although a residual leg length discrepancy necessitated a 6-cm shoe lift. Conservative treatment was maintained for asymptomatic coxa vara and scoliosis.\u003c/p\u003e \u003cp\u003eRegarding Fabry disease, further biochemical analysis confirmed this diagnosis. The patient's plasma α-galactosidase A (GLA) enzyme activity was significantly reduced at 3.88 nmole/hr/mL (reference range: 5.41\u0026ndash;17.99 nmole/hr/mL). Elevated levels of plasma globotriaosylsphingosine (lyso-Gb3) and globotriaosylceramide (Gb3) were observed, measuring 7.2 nM (reference: \u0026lt;2.6 nM) and 12.1 \u0026micro;g/mL (reference: \u0026lt;5.7 \u0026micro;g/mL), respectively. Notably, significant microalbuminuria was detected, with a microalbumin/creatinine ratio of 0.201 (reference: \u0026lt;0.03), indicating renal impairment consistent with Fabry disease. Based on these findings, enzyme replacement therapy for Fabry disease was initiated following diagnosis.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e\n\u003ch3\u003eCase No.2\u003c/h3\u003e\n\u003cp\u003eA 59-year-old female with a known diagnosis of autosomal dominant osteopetrosis presented with a history of cervical myelopathy, chronic pain, and major depressive disorder. The patient's condition was initially identified at age 20 during a routine company health examination, which revealed abnormally high bone density. Between the ages of 30 and 40, she developed progressive headaches and diffuse bone pain, leading to further investigation and confirmation of osteopetrosis. At age 53, she underwent a C3-6 total laminectomy and right T1 hemilaminectomy to relieve spinal compression.\u003c/p\u003e \u003cp\u003eThe patient\u0026rsquo;s chronic pain has been managed with a combination of non-steroidal anti-inflammatory drugs (NSAIDs) and narcotic analgesics, including a fentanyl patch and oxycodone. Adjunctive treatments have included gabapentin and tramadol. Unfortunately, prolonged NSAID use has been associated with the development of chronic kidney disease, further complicating her management.\u003c/p\u003e \u003cp\u003eThe patient's psychiatric history is significant for major depressive disorder, with documented suicide attempts at ages 54 and 57. Her current psychiatric management includes venlafaxine and mirtazapine.\u003c/p\u003e \u003cp\u003ePhysical examination revealed characteristic features of osteopetrosis, including bony protrusions of the forehead, torus palatinus, square-shaped and enlarged mandible. (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e) Radiographic studies confirmed the osteopetrosis diagnosis: skull X-rays demonstrated diffusely thickened skull and spine, while long bone X-ray series showed sclerotic changes with thickened cortical bone without alterations in external shape. (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e) Family history is notable for osteopetrosis, as the patient's father and two younger brothers reportedly experienced similar symptoms (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). Her father passed away during the patient's childhood due to unknown causes. Both younger brothers are deceased, having died by suicide, reportedly due to the intolerable pain associated with this disease. Whole exome sequencing (WES) revealed a missense mutation (c.640G\u0026thinsp;\u0026gt;\u0026thinsp;A, Ala214Try) in the LRP5 gene, consistent with the diagnosis of autosomal dominant osteopetrosis.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e\n\u003ch3\u003eWhole Exome Sequencing (WES) Analysis\u003c/h3\u003e\n\u003cp\u003e Following comprehensive collection of the patient's medical records, family history, and clinical presentations, and after obtaining informed consent and institutional review board approval, a blood sample was collected for genetic analysis. WES was performed on the patient sample following manufacturer-recommended protocols. Genomic DNA was fragmented to an average size of 180\u0026ndash;280 base pairs (bp). Library preparation and target enrichment were conducted using the Illumina platform-compatible Roche KAPA HyperExome kit. Enriched DNA fragments were amplified and sequenced using a 2 x 150 bp Paired-End format on an Illumina NovaSeq platform. Bioinformatics analysis began with sequence alignment using BWA v0.7.17 software, followed by variant calling using GATK v4.1.2.0. Variants were annotated using the MedVar v3.1 database. Variant analysis was performed using Magic Bison (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://magicbison.daopin-inc.com\u003c/span\u003e\u003cspan address=\"https://magicbison.daopin-inc.com\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e), a web-based application developed by Daopin Incorporation. The analytical framework incorporated several principles. Candidate genes were identified based on the patient's phenotypic features using the Human Phenotype Ontology (HPO) and Gene Curation Coalition (GenCC) databases. Variants classified as benign or likely benign in the ClinVar database, or with prevalence exceeding 5% in Common Variation Databases (gnomAD, Allele Frequency Aggregator (ALFA) project, and Taiwan Biobank), were excluded. Genetic variants within the coding sequence (CDS) region were evaluated for potential impacts on protein structure using in silico prediction tools including SIFT, and PROVEAN. Identified variants were clinically interpreted according to the ACMG/AMP 2015 guidelines. Furthermore, variants unrelated to the patient's phenotypic features (not in candidate genes) but reported as pathogenic or likely pathogenic, or with potentially severe consequences (e.g., frameshift or nonsense mutations), and consistent with their inheritance pattern, were displayed in the \"Proactive\" column of Magic Bison.\u003c/p\u003e\n\u003ch3\u003eLiteratures review and analysis of LRP5 mutations\u003c/h3\u003e\n\u003cp\u003e We conducted a comprehensive literature review of LRP5 gene mutations using PubMed to identify all reported LRP5 mutations in peer-reviewed publications. Additionally, we extracted all genetic mutation sites from the Human Gene Mutation Database (HGMD). The data collected from these two sources were integrated and subjected to thorough analysis. Each gene mutation was analyzed and classified according to its associated disease phenotype. Particular emphasis was placed on gene mutations linked to osteoporosis-pseudoglioma syndrome and osteopetrosis. For these disease-causing mutations, we performed in-depth analyses to elucidate why mutations in the same gene can result in contrasting clinical manifestations (osteoporosis versus osteopetrosis). Our aim was to gain insights into the underlying pathogenic mechanisms of these mutations.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eIn case No.1, whole exome sequencing (WES) analysis revealed two variant alleles in the LRP5 gene. The first variant is a missense mutation, c.1385G\u0026thinsp;\u0026gt;\u0026thinsp;A (p.Arg462Gln), located in exon 6 of LRP5. This variant has been previously identified in a patient with familial exudative vitreoretinopathy (FEVR) and is currently classified as a variant of uncertain significance (VUS) [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. The second variant is also a missense mutation, c.1589T\u0026thinsp;\u0026gt;\u0026thinsp;C (p.Ile530Thr), situated in exon 8 of LRP5. This variant was first submitted to ClinVar in 2022, associated with clinical presentations of familial exudative vitreoretinopathy. It is also currently classified as a variant of uncertain significance in ClinVar.\u003c/p\u003e \u003cp\u003eThe c.1385G\u0026thinsp;\u0026gt;\u0026thinsp;A mutation results in the substitution of arginine with glutamine. This change could significantly affect the protein's charge properties, potentially disrupting the formation of ionic bonds. In silico analysis supports the hypothesis that this missense variant has a deleterious effect on protein structure and function. According to the gnomAD dataset, the allele frequency of this variant in Asian populations is as rare as 0.0000116.\u003c/p\u003e \u003cp\u003eThe c.1589T\u0026thinsp;\u0026gt;\u0026thinsp;C mutation results in the substitution of a hydrophobic isoleucine with a hydrophilic threonine, potentially impacting the structural stability and interactions of the protein. In silico analysis suggests this missense variant has a deleterious effect on protein structure and function. The worldwide allele frequency of this variant is 0.000000684 according to the gnomAD dataset, indicating its rarity.\u003c/p\u003e \u003cp\u003eSanger sequencing of the LRP5 gene was conducted on the patient and his parents. The results showed that the patient inherited the c.1589T\u0026thinsp;\u0026gt;\u0026thinsp;C (p.Ile530Thr) variant from the mother, while the c.1385G\u0026thinsp;\u0026gt;\u0026thinsp;A (p.Arg462Gln) variant was inherited from the father (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003eA). Family pedigrees of the patient were shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003eB.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eAlignment of homologous sequences revealed that the affected amino acids in both variants are highly conserved across different species (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eBased on these findings, we strongly suggest that these two mutations are pathogenic loss-of-function variants in the LRP5 gene, contributing to the development of osteoporosis-pseudoglioma syndrome (OPPG).\u003c/p\u003e \u003cp\u003eThrough proactive analysis, we discovered that the patient carries a pathogenic mutation in the GLA gene (c.1066C\u0026thinsp;\u0026gt;\u0026thinsp;T, p.Arg356Trp), associated with the renal variant of Fabry disease. To confirm this finding, Sanger sequencing of the GLA gene was performed on the patient and his mother. The results revealed that the patient inherited this GLA gene mutation from his mother's side. Subsequent family studies identified several family members who also carry this mutation (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). Notably, these individuals were found to have renal impairment consistent with Fabry disease. This incidental finding demonstrates the capacity of comprehensive WGS analysis to uncover clinically relevant genetic variants beyond the primary diagnostic focus, potentially impacting both patient care and familial genetic counseling\u003c/p\u003e \u003cp\u003eIn case No.2, whole exome sequencing (WES) revealed a heterozygous missense mutation (c.640G\u0026thinsp;\u0026gt;\u0026thinsp;A; p.A214T) in exon 3 of the LRP5 gene. This specific mutation has previously been reported to cause the high-bone-mass phenotype [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. The presence of this known pathogenic variant is consistent with the clinical diagnosis of autosomal dominant osteopetrosis.\u003c/p\u003e \u003cp\u003eBased on our comprehensive literature review and analysis of LRP5 mutations, a total of 469 mutation sites in the LRP5 gene have been reported to date. These mutations include 326 missense mutations, 35 nonsense mutations, 32 splicing mutations, 1 regulatory mutation, 41 small deletions, 25 small insertions/duplications, 2 indel mutations, 6 gross deletions, and 1 repeat variation. The most commonly reported mutations in the LRP5 gene are associated with Familial Exudative Vitreoretinopathy (FEVR), with 274 mutations linked to this condition. These mutations are highly suspected to result in loss of function. However, FEVR can also be caused by defects in other genes and conditions [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Furthermore, LRP5-associated FEVR is inherited in an autosomal dominant pattern with incomplete penetrance [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. These factors make it difficult to definitively establish the pathogenicity of many of these mutations. Consequently, they are often classified as variants of uncertain significance, similar to the two mutations identified in our study. Given this uncertainty, we have chosen to exclude FEVR-related mutations from our primary mutation characteristics analysis. This decision allows us to focus on mutations with more clearly established pathogenicity and phenotypic correlations, particularly those associated with bone density disorders such as osteoporosis-pseudoglioma syndrome and osteopetrosis/high bone mass trait.\u003c/p\u003e \u003cp\u003eIn our analysis, mutations associated with osteoporosis-pseudoglioma syndrome (OPPG) were identified at 88 distinct sites. These included 59 point mutations, comprising 41 missense mutations and 18 nonsense mutations. Additionally, we identified 8 splicing mutations, 10 small deletions, 5 small duplications, 4 gross deletions, and 2 small indels. All of these mutations are classified as loss-of-function mutations. Based on the severe phenotype observed in our OPPG patient, the two missense mutations identified (c.1385G\u0026thinsp;\u0026gt;\u0026thinsp;A, p.R462Q; c.1589T\u0026thinsp;\u0026gt;\u0026thinsp;C, p.I560T) are suggested to cause a significant loss of LRP5 function. Because nonsense, frameshift, and splicing mutations are readily understood as loss-of-function mutations, our analysis of loss-of-function mutations specifically focused on missense mutations, as well as in-frame insertion or deletion mutations. There was a total of 42 such mutations, including 41 missense mutations and one in-frame deletion mutation. These mutations are detailed in Fig.\u0026nbsp;\u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e8\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eIn contrast, mutations associated with osteopetrosis, osteosclerosis, and high bone mass traits were identified at 20 distinct mutations, the majority of which were missense mutations (18 out of 20). Notably, no nonsense mutations were observed in this group. Interestingly, one insertion mutation (c.509_514dupGGGGTG, p.G171_E172insGG) and one deletion mutation (c.511_516delGGTGAG, p.G171_E172del) were associated with gain-of-function effects. Both mutations are in-frame, suggesting that the LRP5 protein may retain functional integrity despite these alterations. Nearly all gain-of-function mutations were located in exons 2\u0026ndash;4, with only two mutations (c.4240C\u0026thinsp;\u0026gt;\u0026thinsp;A, p.R1414S and c.4574T\u0026thinsp;\u0026gt;\u0026thinsp;C, p.V1525A) identified in exon 20 and 22 of the LRP5 gene (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003e). The most frequently occurring mutations were c.724G\u0026thinsp;\u0026gt;\u0026thinsp;A, c.512G\u0026thinsp;\u0026gt;\u0026thinsp;T, and c.758C\u0026thinsp;\u0026gt;\u0026thinsp;T, with no significant differences in ethnic distribution. Additionally, mutations in exon 3 appeared to be associated with more severe phenotypes. The mutation c.640G\u0026thinsp;\u0026gt;\u0026thinsp;A (p. A214T) identified in our patient is also located in exon 3 of the LRP5 gene, and her severe phenotype is consistent with this observed trend.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe LRP5 gene plays a critical role in bone metabolism by participating in the Wnt-β-catenin signaling pathway. It encodes a transmembrane co-receptor, LRP5, which partners with the Frizzled receptor to bind Wnt ligands and initiate signaling. This interaction leads to the sequestration of the cytoplasmic destruction complex by the LRP5-Frizzled receptor complex. The destruction complex, which includes proteins such as Axin, APC (adenomatous polyposis coli), GSK-3β (glycogen synthase kinase 3 beta), and CK1 (casein kinase 1), normally regulates β-catenin levels by targeting it for degradation. In the absence of Wnt signaling, the destruction complex facilitates β-catenin's phosphorylation, leading to its ubiquitination and proteasomal degradation, preventing its accumulation (Fig.\u0026nbsp;\u003cspan refid=\"Fig9\" class=\"InternalRef\"\u003e9\u003c/span\u003eA). However, when Wnt ligands bind to the LRP5-Frizzled receptor complex, the destruction complex is sequestered, allowing β-catenin to escape degradation. The accumulated β-catenin then translocates to the nucleus, where it interacts with T-cell factor (TCF)/ lymphoid enhancer factor (LEF) transcription factors to modulate gene expression, promoting bone formation (Fig.\u0026nbsp;\u003cspan refid=\"Fig9\" class=\"InternalRef\"\u003e9\u003c/span\u003eB).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eIn LRP5 loss-of-function mutations, such as in osteoporosis-pseudoglioma syndrome, the lack of functional LRP5 lead Wnt cannot bind LRP5-Frizzled complex result in destruction complex is not appropriately sequestered, leading to continuous β-catenin degradation by destruction complex. This reduces β-catenin levels in the nucleus, decreasing Wnt target gene transcription and impairing bone formation. (Fig.\u0026nbsp;\u003cspan refid=\"Fig9\" class=\"InternalRef\"\u003e9\u003c/span\u003eC)\u003c/p\u003e \u003cp\u003eConversely, in LRP5 gain-of-function mutations (as seen in Osteopetrosis or high bone mass phenotypes), Wnt signaling is abnormally enhanced by specific mechanisms of the mutated LRP5. This leads to the inhibition of the destruction complex, preventing the phosphorylation and degradation of β-catenin. As a result, β-catenin accumulates in the cytoplasm and translocates to the nucleus, where it activates the transcription of Wnt target genes, promoting excessive bone formation through increased osteoblast activity and elevated bone density (Fig.\u0026nbsp;\u003cspan refid=\"Fig9\" class=\"InternalRef\"\u003e9\u003c/span\u003eD, \u003cspan refid=\"Fig9\" class=\"InternalRef\"\u003e9\u003c/span\u003eE).\u003c/p\u003e \u003cp\u003eIt is noteworthy that most gain-of-function mutations are concentrated in exons 2\u0026ndash;4 of the LRP5 gene, with two additional mutations located in exon 20 and 22. This distribution contrasts with that of loss-of-function mutations, which are more widely dispersed throughout the LRP5 gene. This suggests that gain-of-function mutations may occur at specific sites within the LRP5 protein, conferring unique properties that enhance its activity.\u003c/p\u003e \u003cp\u003eIn the regulation of the Wnt signaling pathway, DKK-1 (Dickkopf-1) and SOST (Sclerostin) plays critical roles as inhibitors of bone formation. They function by disrupting the interaction between Wnt ligands and the LRP5 co-receptor, effectively blocking the canonical Wnt pathway. The exons 2\u0026ndash;4 of LRP5 encode the first β-propeller region of the protein's extracellular domain, which serves as the primary binding site for SOST and concurrently influences the interaction of DKK-1 with the third β-propeller region.[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eThese domains are crucial as they form the primary binding sites for SOST. Previous studies have demonstrated that specific amino acid substitutions within these domains of LRP5 can significantly alter its interaction with SOST. Mutations such as D111Y, G171R, A214T, A242T, T253I, and M282V have been shown to reduce the affinity of LRP5 for SOST, thereby facilitating Wnt binding to LRP5 and activating the canonical Wnt pathway, leading to increased bone formation. [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e] In our study, Patient 2 was found to have a c.640G\u0026thinsp;\u0026gt;\u0026thinsp;A (p.A214T) mutation located in exon 3, which results in the substitution of the conserved 214th amino acid in 1st β-propeller domains of LRP5 from alanine to threonine. This mutation is believed to weaken the binding of LRP5 to SOST, thereby enhancing Wnt signaling and promoting bone formation.\u003c/p\u003e \u003cp\u003eTwo gain-of-function mutations located in exons 20 and 22 of the LRP5 gene are believed to induce alterations of the function in the cytoplasmic domain of the receptor protein, which contains five highly conserved PPP-SPxS motifs. Phosphorylation of these motifs is essential for forming the binding site for Axin, a critical component of the destruction complex [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Studies have shown that the c.4574T\u0026thinsp;\u0026gt;\u0026thinsp;C (p.V1525A) mutation enhances the binding of LRP5 to Axin, resulting in the sequestration of the destruction complex. This process allows β-catenin to accumulate, thereby promoting bone formation [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe treatment strategies for Osteoporosis-Pseudoglioma Syndrome (OPPG) primarily focus on symptom management and the prevention of complications, as there is currently no cure for the condition. Bisphosphonate therapy is commonly used in OPPG to inhibit bone resorption and slow down bone loss, with substantial evidence supporting its safety and efficacy in managing the condition [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. Additionally, calcium and vitamin D supplementation are recommended to maintain bone health and enhance the effectiveness of bisphosphonate therapy. Physical therapy and rehabilitation play a crucial role in improving muscle strength and coordination, helping to prevent falls and manage the physical challenges associated with OPPG. Orthopedic interventions are often considered to treat fractures or correct bone deformities that frequently occur in individuals with OPPG. It is important that treatment plans are personalized based on the patient\u0026rsquo;s age, symptom severity, and overall health status, with regular monitoring of bone density and careful management of physical activity being critical aspects of long-term care.\u003c/p\u003e \u003cp\u003eLRP5-related osteopetrosis typically presents a milder clinical course compared to other forms of osteopetrosis [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. However, severe complications can still arise in certain cases, as observed in patient 2 of our cohort. Currently, there are no effective treatments specifically targeting this form of osteopetrosis. LHRH analogues have been explored with the rationale of potentially reducing bone formation by influencing sex hormone levels [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]; however, this approach requires further research to determine its efficacy. As a result, management often centers on monitoring and addressing symptoms as they arise rather than attempting to modify the underlying increased bone density. Treatment plans should be tailored to each patient's specific presentation and symptoms. Symptomatic management, including pain control, should be implemented as necessary. However, caution must be exercised when prescribing analgesics due to their addictive or dependent potential. Additionally, the use of nonsteroidal anti-inflammatory drugs (NSAIDs) should be carefully monitored due to the risk of renal impairment, especially in patients with compromised kidney function. Regular follow-up evaluations, with particular attention to potential neurological complications such as cranial nerve and spinal cord compression, are crucial components of ongoing care. In cases of neurologic compression, timely surgical intervention may be required. This approach underscores the importance of a multidisciplinary care team in managing LRP5-related osteopetrosis, given the current limitations in targeted therapeutic options and the potential for diverse complications.\u003c/p\u003e \u003cp\u003eThe incidental identification of a pathogenic GLA mutation associated with Fabry disease in Patient No. 1 through whole exome sequencing (WES) raises important questions about the potential interplay between Fabry disease and Osteoporosis-Pseudoglioma Syndrome (OPPG). Given the known association between Fabry disease and osteopenia [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e], it is reasonable to consider whether Fabry disease might exacerbate bone issues in patients with Osteogenesis Imperfecta (OPPG). Notably, Case 1 demonstrated frequent fractures and bone deformities that were somewhat more severe than those typically reported in OPPG cases. It remains unclear whether this increased severity is due to the combined effects of Fabry disease or if it results from delayed and inadequate treatment owing to a late diagnosis. This observation highlights the need for further research into the potential synergistic effects of these rare disorders.\u003c/p\u003e \u003cp\u003eThis case highlights the value of comprehensive genetic analysis in clinical practice. The incidentally discovery of Fabry disease through WES not only provides insights into the patient's complex phenotype but also offers significant benefits for the patient's family. By conducting a thorough family tree study, it may be possible to identify other family members with Fabry disease, allowing for early intervention with enzyme replacement therapy (ERT) before the onset of irreversible complications such as renal failure. The utilization of WES or whole genome sequencing (WGS) in this context exemplifies the power of precision medicine. These advanced genetic tools can not only elucidate the genetic basis of clinically apparent conditions but also unveil latent genetic disorders that may have profound implications for patients and their families. The early detection of such conditions can directly benefit individuals by enabling timely interventions and personalized management strategies.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis study underscores the critical role of LRP5 in bone metabolism, as demonstrated by two contrasting cases of LRP5 mutations leading to Osteoporosis-Pseudoglioma Syndrome (OPPG) and osteopetrosis. This report also highlights the importance of WES/WGS in diagnosing and managing complex skeletal disorders, revealing potential synergistic effects between Fabry disease and OPPG, and emphasizing the need for further research into genotype-phenotype correlations. The integration of precision medicine, through tools like WES/WGS, proves invaluable in uncovering latent genetic conditions, ultimately guiding more personalized and effective treatment strategies.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eBMD bone mineral density\u003c/p\u003e\u003cp\u003eDKK-1 Dickkopf-1\u003c/p\u003e\u003cp\u003eFD Fabry disease\u003c/p\u003e\u003cp\u003eFEVR familial exudative vitreoretinopathy\u003c/p\u003e\u003cp\u003eLEF lymphoid enhancer factor\u003c/p\u003e\u003cp\u003eOPPG oteoporosis-pseudoglioma syndrome\u003c/p\u003e\u003cp\u003eSOST Sclerostin\u003c/p\u003e\u003cp\u003eTCF T-cell factor\u003c/p\u003e\u003cp\u003eWES Whole exome sequencing\u003c/p\u003e\u003cp\u003eWGS Whole genome sequencing\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors contributed to the study conception and design, as well as its review and editing. JPH, YHL and JYL performed the systematic review and data collection. HJP, YHL and DMN were major contributors to the writing of the manuscript. CFY, PHW, CKF and CCW contributed to the oversight of the manuscript. All the authors have read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was supported by an industry-academia collaboration project between Taipei Veterans General Hospital and Daopin Incorporation [Grant No.: R2200201], as well as by the Ministry of Science and Technology, Taiwan [Grant No.: NSTC112-2634-F-A49-003-1].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDue to considerations of patient privacy and confidentiality, the datasets produced and examined in the present study are not publicly accessible. Anonymized data can be provided by the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll procedures involving human participants were conducted in accordance with the ethical standards of the Taipei Veterans General Hospital Institutional Review Board, which approved the study (2021-10-001CC). Informed consent was obtained from the participants.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent of publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from all participants, including permission for the use of their photos\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\u003eGong Y, Slee RB, Fukai N, Rawadi G, Roman SR, Reginato AM, et al. LDL Receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell. 2001;107:513\u0026ndash;23.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eXiaona Wang J, Chen H, Xiong X, Yu. Genotype-phenotype associations in familial exudative vitreoretinopathy: A systematic review and meta-analysis on more than 3200 individuals. 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J Pediatr. 2004;144(5 Suppl):S20\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBhatia GS, et al. Severe left ventricular hypertrophy in Anderson-Fabry disease. Heart. 2004;90(10):1136.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZarate YA, Hopkin RJ. Fabry's disease. Lancet. 2008;372(9647):1427\u0026ndash;35.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWeidemann F, et al. Cardiac challenges in patients with Fabry disease. Int J Cardiol. 2010;141(1):3\u0026ndash;10.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNakao S, et al. An atypical variant of Fabry's disease in men with left ventricular hypertrophy. N Engl J Med. 1995;333(5):288\u0026ndash;93.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKotanko P, et al. Results of a nationwide screening for Anderson-Fabry disease among dialysis patients. 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Genet Med. 2007;9(12):812\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTao T, Xu N, Li J, Li H, Qu J, Yin H, Liang J, Zhao M. Xiaoxin Li, and Lvzhen Huang. Ocular Features and Mutation Spectrum of Patients With Familial Exudative Vitreoretinopathy. Invest Ophthalmol Vis Sci. 2021;62(15):4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVan Wesenbeeck L, Cleiren E, Gram J, Beals RK, B\u0026eacute;nichou O, Scopelliti D, Key L, Renton T, Bartels C, Gong Y, Warman ML, De Vernejoul MC, Bollerslev J, Van Hul W. Six novel missense mutations in the LDL receptor-related protein 5 (LRP5) gene in different conditions with an increased bone density. Am J Hum Genet. 2003;72(3):763\u0026ndash;71.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHiroyuki Kondo. Complex genetics of familial exudative vitreoretinopathy and related pediatric retinal detachments. Taiwan J Ophthalmol. 2015;5(2):56\u0026ndash;62.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLuo J, Li J, Zhang X, Li JK, Chen HJ, Zhao PQ, Fei P. Five novel copy number variations detected in patients with familial exudative vitreoretinopathy. Mol Vis. 2021;27:632\u0026ndash;42.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhao D, Sun L, Jing WZ, Wang HBZO, Jiang Y, Xia W. Xiaoping Xing, and Mei Li. Novel mutation in LRP5 gene cause rare osteosclerosis: cases studies and literature review. Mol Genet Genomics. 2023;298(3):683\u0026ndash;92.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAi M, Heeger S, Bartels CF, Schelling DK. Osteoporosis-Pseudoglioma Collaborative Group Clinical and molecular findings in osteoporosis-pseudoglioma syndrome. Am J Hum Genet. 2005;77:741\u0026ndash;53.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHa\u0026yuml; E, Buczkowski T, Marty C, et al. Peptide-based mediated disruption of N-cadherin-LRP5/6 interaction promotes Wnt signaling and bone formation. J Bone Min Res. 2012;27(9):1852\u0026ndash;63.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGuo J, Cooper LF. Influence of an LRP5 cytoplasmic SNP on Wnt signaling and osteoblastic differentiation. Bone. 2007;40(1):57\u0026ndash;67.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStreeten EA, McBride D, Puffenberger E, Hoffman ME, Pollin TI, Donnelly P, Sack P, Morton H. Osteoporosis-pseudoglioma syndrome: description of 9 new cases and beneficial response to bisphosphonates. Bone. 2008;43(3):584\u0026ndash;90.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIordanis Papadopoulos E, Bountouvi A, Attilakos E, Gole A, Dinopoulos M, Peppa. Polyxeni Nikolaidou \u0026amp; Anna Papadopoulou. Osteoporosis-pseudoglioma syndrome: clinical, genetic, and treatment-response study of 10 new cases in Greece. Eur J Pediatr. 2019;178(3):323\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKhan MA, Ullah A, Naeem M. Whole exome sequencing identified two novel homozygous missense variants in the same codon of CLCN7 underlying autosomal recessive infantile malignant osteopetrosis in a Pakistani family. Mol Biol Rep. 2018;45(4):565\u0026ndash;70.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEl-Kamah GY, Mehrez MI, Taher MB, El-Bassyouni HT, Gaber KR, Amr KS. Outlining the Clinical Profile of TCIRG1 14 Variants including 5 Novels with Overview of ARO Phenotype and Ethnic Impact in 20 Egyptian Families. Genes (Basel). 2023;14(4):900.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJafri SM, Burke EA, Adams DR, Evans C, Bulas D, Weinerman SA, Pan K, Collins MT, Markello TC, Vezina G, Gahl WA, Toro C. Potential therapeutic response in a severe case of autosomal dominant osteopetrosis type I. J Transl Genet Genom. 2022;6:281\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGermain DP. Osteopenia and osteoporosis: previously unrecognized manifestations of Fabry disease. Clin Genet. 2005;68:93\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"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":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Osteoporosis pseudoglioma syndrome, Osteopetrosis, Fabry disease, LRP5, whole exome sequencing","lastPublishedDoi":"10.21203/rs.3.rs-5329332/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5329332/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground:\u003c/h2\u003e \u003cp\u003eThis study explores the critical role of LRP5 gene mutations in bone metabolism by presenting two cases of rare inherited disorders with contrasting skeletal manifestations. The study aims to highlight the spectrum of LRP5-associated disorders through the analysis of these cases.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe first case involves a male patient with osteoporosis-pseudoglioma syndrome (OPPG) who has compound heterozygous missense mutations in LRP5 (c.1385G\u0026thinsp;\u0026gt;\u0026thinsp;A and c.1589T\u0026thinsp;\u0026gt;\u0026thinsp;C), each inherited from a different parent. These mutations, previously linked only to exudative vitreoretinopathy and classified as variants of uncertain significance, are now reclassified as pathogenic for OPPG. Additionally, whole-exome sequencing identified an incidental pathogenic mutation (c.1066C\u0026thinsp;\u0026gt;\u0026thinsp;T) in the GLA gene, indicating comorbid Fabry disease, which is associated with an increased risk of osteopenia. The second case involves a female patient diagnosed with osteopetrosis, who carries a missense mutation (c.640G\u0026thinsp;\u0026gt;\u0026thinsp;A) in LRP5, exemplifying the opposite end of the bone density spectrum.\u003c/p\u003e\u003ch2\u003eConclusions:\u003c/h2\u003e \u003cp\u003eThis study underscores the diverse skeletal manifestations associated with LRP5 mutations and provides valuable insights into genotype-phenotype correlations. By comparing LRP5 mutations linked to osteosclerosis and OPPG, this research enhances the understanding of LRP5-associated disorders.\u003c/p\u003e","manuscriptTitle":"Contrasting LRP5 Mutations in Osteoporosis-Pseudoglioma Syndrome and Osteopetrosis: Case Reports and Literature Review.","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-12-19 18:32:29","doi":"10.21203/rs.3.rs-5329332/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d367284b-c2fa-4660-9e59-28951a66ff3a","owner":[],"postedDate":"December 19th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-12-27T04:10:20+00:00","versionOfRecord":[],"versionCreatedAt":"2024-12-19 18:32:29","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5329332","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5329332","identity":"rs-5329332","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}