Mutational Analysis of CLC-5, Cofilin and CLC-4 in Patients with Dent's Disease
Mutational Analysis of CLC-5, Cofilin and CLC-4 in Patients with Dent's Disease
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DOI：
10.1159/000225944
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发表时间：
2009-01-01
影响因子：
--
通讯作者：
Thakker, Rajesh V.
中科院分区：
文献类型：
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作者：
Wu, Fiona;Reed, Anita A. C.;Thakker, Rajesh V.
背景/目的：邓氏病是由氯离子/质子反转运蛋白CLC-5或眼-脑-肾-洛氏综合征（OCRL1）基因突变引起的。方法：对18例邓特病先证者进行CLC-5及其相互作用蛋白CLC-4和cofilin的突变检测。在肾细胞中检测野生型和突变型clc -5。研究了一个家庭口服补钙后尿钙排泄情况。结果：8例患者共检测到7种不同的CLC-5突变，包括2种无义突变（Arg347Stop和Arg718Stop）、2种错义突变（Ser244Leu和Arg516Trp）、1种内含子3供体剪接位点突变、1种缺失插入（nt930delTCinsA）和1种帧内缺失（523delVal）。在其余10例患者中，在CLC-4或cofilin编码区未检测到DNA序列异常，并独立排除了OCRL1。有CLC-5突变的患者在表型上与没有突变的患者相似。供体剪接位点CLC-5突变导致外显子3跳变。电生理学表明，523delVal CLC-5突变消除了CLC-5介导的氯离子电导。60%的CLC-5缺失插入的女性患有肾结石，尽管口服补钙前后的钙排泄与未受影响的女性相似。结论：在该患者队列中，发现了三个新的CLC-5突变，排除了crl1、CLC-4和cofilin突变导致邓特病。版权所有(C) 2009 S. Karger AG，巴塞尔
Background/Aims: Dent's disease is caused by mutations in the chloride/proton antiporter, CLC-5, or oculo-cerebro-renal-syndrome-of-Lowe (OCRL1) genes. Methods: Eighteen probands with Dent's disease were investigated for mutations in CLC-5 and two of its interacting proteins, CLC-4 and cofilin. Wild-type and mutant CLC-5s were assessed in kidney cells. Urinary calcium excretion following an oral calcium challenge was studied in one family. Results: Seven different CLC-5 mutations consisting of two nonsense mutations (Arg347Stop and Arg718Stop), two missense mutations (Ser244Leu and Arg516Trp), one intron 3 donor splice site mutation, one deletion-insertion (nt930delTCinsA) and an in-frame deletion (523delVal) were identified in 8 patients. In the remaining 10 patients, DNA sequence abnormalities were not detected in the coding regions of CLC-4 or cofilin, and were independently excluded for OCRL1. Patients with CLC-5 mutations were phenotypically similar to those without. The donor splice site CLC-5 mutation resulted in exon 3 skipping. Electrophysiology demonstrated that the 523delVal CLC-5 mutation abolished CLC-5-mediated chloride conductance. Sixty percent of women with the CLC-5 deletion-insertion had nephrolithiasis, although calcium excretion before and after oral calcium challenge was similar to that in unaffected females. Conclusions: Three novel CLC-5 mutations were identified, and mutations in OCRL1, CLC-4 and cofilin excluded in causing Dent's disease in this patient cohort. Copyright (C) 2009 S. Karger AG, Basel