Guleray Lafci Naz, van Goor Mark, Cetinkaya Semra, van der Wijst Jenny, Acun Melisa, Kurt Colak Fatma, Cetinkaya Arda, Hoenderop Joost
Hacettepe University, Medical Faculty, Department of Medical Genetics, Ankara, Turkey.
Health Science University, Dr. Sami Ulus Obstetrics and Gynecology, Children Health and Disease Training and Research Hospital, Department of Medical Genetics, Ankara, Turkey.
Eur J Hum Genet. 2024 Nov;32(11):1506-1514. doi: 10.1038/s41431-024-01589-9. Epub 2024 Mar 25.
Hypercalciuria is the most common metabolic risk factor in people with kidney stone disease. Its etiology is mostly multifactorial, although monogenetic causes of hypercalciuria have also been described. Despite the increased availability of genetic diagnostic tests, the vast majority of individuals with familial hypercalciuria remain unsolved. In this study, we investigated a consanguineous pedigree with idiopathic hypercalciuria. The proband additionally exhibited severe skeletal deformities and hyperparathyroidism. Whole-exome sequencing of the proband revealed a homozygous ultra-rare variant in TRPV5 (NM_019841.7:c.1792G>A; p.(Val598Met)), which encodes for a renal Ca-selective ion channel. The variant segregates with the three individuals with hypercalciuria. The skeletal phenotype unique to the proband was due to an additional pathogenic somatic mutation in GNAS (NM_000516.7:c.601C>T; p.(Arg201Cys)), which leads to polyostotic fibrous dysplasia. The variant in TRPV5 is located in the TRP helix, a characteristic amphipathic helix that is indispensable for the gating movements of TRP channels. Biochemical characterization of the TRPV5 p.(Val598Met) channel revealed a complete loss of Ca transport capability. This defect is caused by reduced expression of the mutant channel, due to misfolding and preferential targeting to the proteasome for degradation. Based on these findings, we conclude that biallelic loss of TRPV5 function causes a novel form of monogenic autosomal recessive hypercalciuria, which we name renal Ca-wasting hypercalciuria (RCWH). The recessive inheritance pattern explains the rarity of RCWH and underscores the potential prevalence of RCWH in highly consanguineous populations, emphasizing the importance of exploration of this disorder within such communities.
高钙尿症是肾结石病患者中最常见的代谢风险因素。其病因大多是多因素的，尽管也有高钙尿症的单基因病因被描述。尽管基因诊断测试的可用性有所提高，但绝大多数家族性高钙尿症患者的病因仍未明确。在本研究中，我们调查了一个患有特发性高钙尿症的近亲家系。先证者还表现出严重的骨骼畸形和甲状旁腺功能亢进。对先证者进行全外显子测序发现，TRPV5（NM_019841.7:c.1792G>A；p.(Val598Met)）存在纯合的超罕见变异，该基因编码一种肾脏钙选择性离子通道。该变异与三名高钙尿症患者共分离。先证者独特的骨骼表型是由于GNAS（NM_000516.7:c.601C>T；p.(Arg201Cys)）中另一个致病性体细胞突变所致，该突变导致多骨纤维发育不良。TRPV5中的变异位于TRP螺旋中，这是一种特征性的两亲性螺旋，对于TRP通道的门控运动不可或缺。对TRPV5 p.(Val598Met)通道的生化特性分析显示其钙转运能力完全丧失。这种缺陷是由于突变通道的表达减少所致，原因是错误折叠和优先靶向蛋白酶体进行降解。基于这些发现，我们得出结论，TRPV5功能的双等位基因缺失导致了一种新型的单基因常染色体隐性高钙尿症，我们将其命名为肾性钙流失性高钙尿症（RCWH）。隐性遗传模式解释了RCWH的罕见性，并强调了RCWH在高度近亲人群中的潜在患病率，突出了在这些群体中探索这种疾病的重要性。
