Mutation Update of the CLCN5 Gene Responsible for Dent Disease 1
Mutation Update of the CLCN5 Gene Responsible for Dent Disease 1
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DOI：
10.1002/humu.22804
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发表时间：
2015-08-01
期刊：
影响因子：
3.9
通讯作者：
Vargas-Poussou, Rosa
中科院分区：
文献类型：
--
作者：
Mansour-Hendili, Lamisse;Blanchard, Anne;Vargas-Poussou, Rosa
Dent病是一种罕见的X-连锁肾小管病变，其特征为低分子量蛋白尿、高钙尿、肾钙质沉着症和/或肾结石、进行性肾衰竭和其他近端小管功能障碍的各种表现。它通常在几十年内进展为慢性肾功能不全，因此分子表征对于进行适当的遗传咨询很重要。迄今为止已经描述了两种遗传亚型：1型牙病由编码氯离子/质子交换剂ClC-5的CLCN 5基因突变引起; 2型牙病由编码肌醇多磷酸5-磷酸酶OCRL-1的OCRL基因突变引起。在此，我们回顾了以前报道的突变（n = 192）和他们的相关表型在377例男性患者与Dent病1和描述表型和新的（n = 42）和复发突变（n = 24）在一个大的队列117 Dent病1患者属于90个家庭。描述的新的错义和框内突变被映射到一个三维同源模型的ClC-5蛋白。该分析表明这些突变影响二聚化过程、螺旋稳定性或转运。我们队列患者的表型支持并扩展了在较小研究中报告的表型。
Dent disease is a rare X-linked tubulopathy characterized by low molecular weight proteinuria, hypercalciuria, nephrocalcinosis and/or nephrolithiasis, progressive renal failure, and variable manifestations of other proximal tubule dysfunctions. It often progresses over a few decades to chronic renal insufficiency, and therefore molecular characterization is important to allow appropriate genetic counseling. Two genetic subtypes have been described to date: Dent disease 1 is caused by mutations of the CLCN5 gene, coding for the chloride/proton exchanger ClC-5; and Dent disease 2 by mutations of the OCRL gene, coding for the inositol polyphosphate 5-phosphatase OCRL-1. Herein, we review previously reported mutations (n = 192) and their associated phenotype in 377 male patients with Dent disease 1 and describe phenotype and novel (n = 42) and recurrent mutations (n = 24) in a large cohort of 117 Dent disease 1 patients belonging to 90 families. The novel missense and in-frame mutations described were mapped onto a three-dimensional homology model of the ClC-5 protein. This analysis suggests that these mutations affect the dimerization process, helix stability, or transport. The phenotype of our cohort patients supports and extends the phenotype that has been reported in smaller studies.