Chloride channel CLCN5 mutations in Japanese children with familial idiopathic low molecular weight proteinuria
Chloride channel CLCN5 mutations in Japanese children with familial idiopathic low molecular weight proteinuria
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DOI：
10.1046/j.1523-1755.1999.00231.x
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发表时间：
1999-01-01
影响因子：
19.6
通讯作者：
Hattori, S
中科院分区：
文献类型：
--
作者：
Nakazato, H;Yoshimuta, J;Hattori, S
背景家族性特发性低分子量蛋白尿（FamilialIdiopathicLowmolecularweightProteinuria，FILMWP）是一种以轻度蛋白尿为特征的肾近端小管病变，多发生于年轻人，无佝偻病，肾功能相对保守。肾氯离子通道CLCN 5基因的突变已被报道在三种疾病的高尿钙肾结石和FILMWP。为了评估分子缺陷和表型变异之间的关系，我们采用单链构象多态性和测序分析了另外三个日本FILMWP家族的CLCN 5基因。我们发现了三个突变：密码子514处的单碱基插入;密码子116处的单碱基缺失;以及无义突变R704 X。R704 X突变与X连锁隐性肾结石中发现的相同，但我们的患者没有肾功能衰竭。前两个突变引起阅读框的移位，并且都引入了提前终止密码子，导致分别缺少220（29%）、610（82%）和43（6%）个氨基酸的截短的CLC-5蛋白的合成。这些突变被证明与疾病共分离在每个三个家庭。我们的结论是，CLCN 5基因是负责在许多日本家庭的肾近端小管病变，并建议，分子缺陷，环境因素，或其他修饰基因可能占不同的表型。
Background Familial idiopathic low molecular weight proteinuria (FILMWP) is a renal proximal tubulopathy characterized by mild proteinuria consisting of low molecular weight proteinuria and relatively conserved renal function in young patients, but without rickets. Mutations in the renal chloride channel CLCN5 gene have been reported in three disorders of hypercalciuric nephrolithiasis and in FILMWP.Methods. To assess the relationship between molecular defects and phenotypic variations, we analyzed the CLCN5 gene from three additional Japanese families with FILMWP using single-strand conformation polymorphism and sequencing.Results. We identified three mutations: a single base insertion at codon 514; a single base deletion at codon 116; and a nonsense mutation, R704X. The R704X mutation is identical to that found in X-linked recessive nephrolithiasis, but there was no renal failure in our patient. The first two mutations caused a shift in the reading frame, and all introduced a premature stop codon, resulting in synthesis of truncated CLC-5 proteins that lacked 220 (29%), 610 (82%), and 43 (6%) amino acids, respectively. These mutations were demonstrated to cosegregate with the disease in each of the three families.Conclusions. We conclude that the CLCN5 gene is responsible for the renal proximal tubulopathy in many Japanese families and suggest that molecular defects, environmental factors, or other modifying genes may account for the different phenotypes.