Reversed polarized delivery of an aquaporin-2 mutant causes dominant nephrogenic diabetes insipidus.
Reversed polarized delivery of an aquaporin-2 mutant causes dominant nephrogenic diabetes insipidus.
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DOI：
10.1083/jcb.200309017
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发表时间：
2003-12-08
影响因子：
7.8
通讯作者：
Deen, Peter M T
中科院分区：
文献类型：
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作者：
Kamsteeg, Erik-Jan;Bichet, Daniel G;Konings, Irene B M;Nivet, Hubert;Lonergan, Michelle;Arthus, Marie-Francoise;van Os, Carel H;Deen, Peter M T
加压素通过将水通道蛋白-2（AQP 2）水通道从细胞内囊泡重新分配到肾集合管的顶面，导致从尿液中重吸收水，从而调节身体水分保存。AQP 2突变导致常染色体肾源性尿崩症（NDI），这是一种以不能浓缩尿液为特征的疾病。在这里，我们报告了一个移码突变AQP 2导致显性NDI。这种AQP 2突变体在非洲爪蟾卵母细胞中表达时是一种功能性水通道。然而，在极化的肾细胞中表达，它被错误地路由到基底外侧而不是顶端质膜。此外，该突变体与野生型AQP 2形成异源四聚体，并将该复合物重定向至基底外侧表面。移码诱导AQP 2的COOH末端发生变化，产生基于亮氨酸和酪氨酸的基序，这导致AQP 2的反向分选。我们的数据揭示了显性NDI的一种新的细胞表型，并表明突变亚基中基底外侧分选基序的优势可能是疾病的分子基础。
Vasopressin regulates body water conservation by redistributing aquaporin-2 (AQP2) water channels from intracellular vesicles to the apical surface of renal collecting ducts, resulting in water reabsorption from urine. Mutations in AQP2 cause autosomal nephrogenic diabetes insipidus (NDI), a disease characterized by the inability to concentrate urine. Here, we report a frame-shift mutation in AQP2 causing dominant NDI. This AQP2 mutant is a functional water channel when expressed in Xenopus oocytes. However, expressed in polarized renal cells, it is misrouted to the basolateral instead of apical plasma membrane. Additionally, this mutant forms heterotetramers with wild-type AQP2 and redirects this complex to the basolateral surface. The frame shift induces a change in the COOH terminus of AQP2, creating both a leucine- and a tyrosine-based motif, which cause the reversed sorting of AQP2. Our data reveal a novel cellular phenotype in dominant NDI and show that dominance of basolateral sorting motifs in a mutant subunit can be the molecular basis for disease.