Praditsap Oranud, Ahsan Nawara Faiza, Nettuwakul Choochai, Sawasdee Nunghathai, Sritippayawan Suchai, Yenchitsomanus Pa-Thai, Rungroj Nanyawan
Division of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
Immunology Graduate Program, Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
Urolithiasis. 2024 Dec 16;53(1):7. doi: 10.1007/s00240-024-01674-0.
Kidney stone disease (KSD) is a prevalent and complex condition, with an incidence of 85 cases per 100,000 individuals in Thailand. Notably, over 40% of cases are concentrated in the northeastern region, indicating a potential genetic influence, which is supported by genetic mutations reported in several families by our research group. Despite this, the genetic basis of KSD remains largely unknown for many Thai families. This study aimed to identify the genetic mutation responsible for KSD in a specific Thai family, the UBRS131 family, which includes four affected individuals. Whole exome sequencing was performed, and variant filtering using the VarCards2 program identified 10 potentially causative mutations across 9 genes. These mutations were subjected to segregation analysis among family members and screened in 180 control and 179 case samples using real-time PCR-HRM or PCR-RFLP techniques. Prioritization of these variants using GeneDistiller identified the p.Asp775Glu mutation in the heparan sulfate proteoglycan 2 (HSPG2) gene as the likely causative mutation for KSD in this family. The Asp775 residue is highly conserved across vertebrates, and structural analysis suggests that the Glu775 substitution may disrupt the formation of two crucial hydrogen bonds, potentially altering the mutant protein's configuration. Immunohistochemistry confirmed the presence of perlecan (HSPG2 protein) in the proximal tubules in nephrons. These findings highlight the significant role of the HSPG2 gene in familial KSD within this study family.
肾结石病（KSD）是一种常见且复杂的病症，在泰国每10万人中有85例发病。值得注意的是，超过40%的病例集中在东北地区，这表明可能存在遗传影响，我们研究小组在几个家族中报告的基因突变也支持了这一点。尽管如此，许多泰国家族中KSD的遗传基础在很大程度上仍然未知。本研究旨在确定一个特定泰国家族——UBRS131家族中导致KSD的基因突变，该家族中有四名患者。进行了全外显子组测序，使用VarCards2程序进行变异筛选，在9个基因中鉴定出10个潜在的致病突变。对这些突变在家庭成员中进行分离分析，并使用实时PCR-HRM或PCR-RFLP技术在180个对照样本和179个病例样本中进行筛选。使用GeneDistiller对这些变异进行优先级排序，确定硫酸乙酰肝素蛋白聚糖2（HSPG2）基因中的p.Asp775Glu突变为该家族中KSD的可能致病突变。Asp775残基在脊椎动物中高度保守，结构分析表明Glu775替代可能会破坏两个关键氢键的形成，从而可能改变突变蛋白的构象。免疫组织化学证实了在肾单位近端小管中存在基底膜聚糖（HSPG2蛋白）。这些发现突出了HSPG2基因在本研究家族的家族性KSD中的重要作用。
