Characterization of renal chloride channel (CLCN5) mutations in Dent's disease

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Item Type:	Article
Title:	Characterization of renal chloride channel (CLCN5) mutations in Dent's disease
Creators Name:	Yamamoto, K., Cox, J.P., Friedrich, T., Christie, P.T., Bald, M., Houtman, P.N., Lapsley, M.J., Patzer, L., Tsimaratos, M., Van'T Hoff, W.G., Yamaoka, K., Jentsch, T.J. and Thakker, R.V.
Abstract:	Dent's disease is an X-linked renal tubular disorder characterized by low molecular weight proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis, and renal failure. The disease is caused by mutations in a renal chloride channel gene, CLCN5, which encodes a 746 amino acid protein (CLC-5), with 12 to 13 transmembrane domains. In this study, an additional six unrelated patients with Dent's disease were identified and investigated for CLCN5 mutations by DNA sequence analysis of the 11 coding exons of CLCN5. This revealed six mutations: four frameshift deletions involving codons 392, 394, 658, and 728, one nonsense mutation (Tyr617Stop), and an A to T transversion at codon 601 that would result in either a missense mutation (Asp601Val) or creation of a novel donor splice site. These mutations were confirmed by restriction endonuclease or sequence-specific oligonucleotide hybridization analysis and were not common polymorphisms. The frameshift deletions and nonsense mutation predict truncated and inactivated CLC-5. The effects of the putative missense Asp601Val mutant CLC-5 were assessed by heterologous expression in XENOPUS: oocytes, and this revealed a chloride conductance that was similar to that observed for wild-type CLC-5. However, an analysis of the mutant CLCN5 transcripts revealed utilization of the novel donor splice site, resulting in a truncated CLC-5. Thus, all of the six mutations are likely to result in truncated CLC-5 and a loss of function, and these findings expand the spectrum of CLCN5 mutations associated with Dent's disease.
Keywords:	Amino Acid Sequence, Base Sequence, Chloride Channels, DNA, Frameshift Mutation, Gene Deletion, Gene Expression, Kidney, Kidney Diseases, Kidney Tubules, Mutation, Missense Mutation, Oocytes, Pedigree, Animals, Xenopus
Source:	Journal of the American Society of Nephrology
ISSN:	1046-6673
Publisher:	American Society of Nephrology
Volume:	11
Number:	8
Page Range:	1460-1468
Date:	August 2000
Official Publication:	http://jasn.asnjournals.org/cgi/content/abstract/11/8/1460
PubMed:	View item in PubMed

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