A novel claudin 16 mutation associated with childhood hypercalciuria abolishes binding to ZO-1 and results in lysosomal mistargeting
A novel claudin 16 mutation associated with childhood hypercalciuria abolishes binding to ZO-1 and results in lysosomal mistargeting
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DOI：
10.1086/380418
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发表时间：
2003-12-01
影响因子：
9.8
通讯作者：
Hunziker, W
中科院分区：
文献类型：
--
作者：
Müller, D;Kausalya, PJ;Hunziker, W
肾紧密连接蛋白claudin 16基因编码突变导致家族性低镁血症伴高钙尿症和肾钙化症，这是一种肾Ca2+和Mg2+处理的常染色体隐性遗传病，逐渐导致慢性肾衰竭，在杂合携带者中有肾结石的报道。筛选了11个特发性高钙尿症家族的队列，在两个家族中发现了claudin 16基因的新型纯合突变。与家族性低镁血症合并高钙尿和肾钙质沉着症的典型症状相反，这些患者表现出严重但自限性的儿童期高钙尿，肾小球滤过率保持不变。突变导致pdz结构域结合基序失活，从而使紧密连接支架蛋白ZO-1与claudin 16的关联失效。与野生型claudin 16相反，突变体不再局限于肾上皮细胞的紧密连接，而是在溶酶体中积累。因此，claudin 16基因不同基因内位点的突变可能导致具有不同预后的特定临床表型。claudin 16的突变会影响。与ZO-1的相互作用导致溶酶体错标，首次提供了我们对claudin 16基因疾病相关突变的分子机制的了解。
Mutations in the gene coding for the renal tight junction protein claudin 16 cause familial hypomagnesemia with hypercalciuria and nephrocalcinosis, an autosomal recessive disorder of renal Ca2+ and Mg2+ handling that progressively leads to chronic renal failure, with nephrolithiasis having been reported in heterozygous carriers. Screening a cohort of 11 families with idiopathic hypercalciuria identified a novel homozygous mutation in the claudin 16 gene in two families. In contrast to classical symptoms of familial hypomagnesemia with hypercalciuria and nephrocalcinosis, the patients displayed serious but self-limiting childhood hypercalciuria with preserved glomerular filtration rate. The mutation results in inactivation of a PDZ-domain binding motif, thereby disabling the association of the tight junction scaffolding protein ZO-1 with claudin 16. In contrast to wild-type claudin 16, the mutant no longer localizes to tight,junctions in kidney epithelial cells but instead accumulates in lysosomes. Thus, mutations at different intragenic sites in the claudin 16 gene may lead to particular clinical phenotypes with a distinct prognosis. Mutations in claudin 16 that affect. interaction with ZO-1 lead to lysosomal mistargeting, providing-for the first time, to our knowledge-insight into the molecular mechanism of a disease-associated mutation in the claudin 16 gene.