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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Congenital progressive hydronephrosis (cph) is caused by an S256L mutation in aquaporin-2 that affects its phosphorylatiora and apical membrane accumulation
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Congenital progressive hydronephrosis (cph) is caused by an S256L mutation in aquaporin-2 that affects its phosphorylatiora and apical membrane accumulation

机译：先天性进行性肾积水（cph）是由aquaporin-2的S256L突变引起的，该突变影响其磷酸化和顶膜积累

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Congenital progressive hydronephrosis (cph) is a spontaneous recessive mutation that causes severe hydronephrosis and obstructive nephropathy in affected mice. The mutation has been mapped to the distal end of mouse chromosome 15, but the mutated gene has not been found. Here, we describe the identification of a single base pair change in aquaporin-2 (Aqp2) in cph mutants through genetic linkage mapping. The C-T change led to the substitution of a Ser (5256) by a Leu in the cytoplasmic tail of the Aqp2 protein, preventing its phosphorylation at 5256 and the subsequent accumulation of Aqp2 on the apical membrane of the collecting duct principal cells. The interference with normal trafficking of Aqp2 by this mutation resulted in a severe urine concentration defect. cph homozygotes demonstrated polydipsia and produced a copious amount of hypotonic urine. The urine concentration defect could not be corrected by [deamino-Cys(1),D-Arg8]-vasopressin (DDAVP, a vasopressin analog), characteristic of nephrogenic diabetes insipidus. The nephrogenic diabetes insipidus symptoms and the absence of developmental defects in the pyeloureteral peristaltic machinery in the mutants before the onset of hydronephrosis suggest that the congenital obstructive nephropathy is most likely a result of the polyuria. This study has revealed the genetic basis for the classical cph mutation and has provided direct genetic evidence that 5256 in Aqp2 is indispensable for the apical accumulation, but not the general glycosylation or membrane association, of Aqp2.
机译：先天性进行性肾积水（cph）是一种自发的隐性突变，会在受影响的小鼠中引起严重的肾积水和阻塞性肾病。该突变已被定位到小鼠15号染色体的远端，但尚未发现该突变的基因。在这里，我们描述了通过遗传连锁图谱鉴定cph突变体中aquaporin-2（Aqp2）中单个碱基对的变化。 C-T变化导致Aqp2蛋白胞质尾中的Leu取代Ser（5256），阻止其在5256处的磷酸化，以及随后Aqp2在收集管主要细胞的顶膜上积聚。该突变对Aqp2正常运输的干扰导致严重的尿液浓度缺陷。 cph纯合子表现为多饮，并产生了大量的低渗尿。尿液浓度缺陷不能通过[deamino-Cys（1），D-Arg8]-加压素（DDAVP，一种加压素类似物）来纠正，这是肾性尿崩症的特征。在肾积水发生之前，突变体的肾源性尿崩症症状和肾盂输尿管蠕动机械缺乏发育缺陷提示，先天性阻塞性肾病很可能是多尿症的结果。这项研究揭示了经典cph突变的遗传基础，并提供了直接的遗传学证据，表明Aqp2中的5256对于Aqp2的顶端积累是不可缺少的，而不是一般的糖基化或膜结合。

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