Novel truncating mutations in the ClC-5 chloride channel gene in patients with Dent's disease

Carballo‐Trujillo, Irma; García‐Nieto, Victor; Moya‐Angeler, Francisco J.; Antón‐Gamero, Montserrat; Loris, C; Méndez-Álvarez, Sebastián; Claverie-Martı́n, Félix

doi:10.1093/ndt/gfg016

Cited by 31 publications

(21 citation statements)

References 18 publications

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“…Three of these mutations were novel and consisted of a donor splice site mutation, a deletion-insertion that resulted in a frameshift and an in-frame 3-bp deletion. The remaining mutations consisted of two missense (Ser244Leu and Arg516Trp) and two nonsense (Arg347Stop and Arg718Stop) mutations that have previously been reported in other unrelated patients with Dent’s disease [3, 6, 23]. All of these CLCN5 mutations were confirmed by either restriction endonuclease analysis (fig.…”

Section: Resultsmentioning

confidence: 64%

“…1), the in-frame deletion (523delVal) and the donor splice site mutation (fig. 2) represent novel CLCN5 mutations, whereas the missense (Ser244Leu and Arg516Trp) and nonsense mutations (Arg347Stop and Arg718Stop) occur in other unrelated patients with Dent’s disease [3,4,5,6, 23, 27,32,33,34,35,36,37]. The total number of CLCN5 mutations now published, including the results of our present study, is 148, and these are scattered throughout the coding region, with no evidence for major mutational hot spots [27, 28, 34,37,38,39,40,41].…”

Section: Discussionmentioning

confidence: 99%

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Mutational Analysis of CLC-5, Cofilin and CLC-4 in Patients with Dent’s Disease

Reed²,

Williams³

et al. 2009

Nephron Physiol

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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.

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Section: Resultsmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 99%

Mutational Analysis of CLC-5, Cofilin and CLC-4 in Patients with Dent’s Disease

Reed²,

Williams³

et al. 2009

Nephron Physiol

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“…Different types of disease-causing mutations in the CLCN5 gene have been reported (Lloyd et al 1996;Hoopes et al 1998;Morimoto et al 1998;Yamamoto et al 2000;Carballo-Trujillo et al 2003;ClaverieMartin et al 2003;Ludwig et al 2005). Most of these mutations are single nucleotide substitutions that are scattered throughout the coding sequence of the gene.…”

Section: Introductionmentioning

confidence: 99%

A missense mutation in the chloride/proton ClC-5 antiporter gene results in increased expression of an alternative mRNA form that lacks exons 10 and 11. Identification of seven new CLCN5 mutations in patients with Dent’s disease

et al. 2007

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Mutations in the voltage-gated chloride/ proton antiporter ClC-5 gene, CLCN5, are associated with Dent's disease, an X-linked renal tubulopathy. Our interest is to identify and characterize diseasecausing CLCN5 mutations, especially those that alter the splicing of the pre-mRNA. We analyzed the CLCN5 gene from nine unrelated Spanish Dent's disease patients and their relatives by DNA sequencing. Pre-mRNA splicing analysis was performed by RT-PCR. Seven new mutations were identified, consisting of three missense mutations (C219R, F273L, and W547G), one splice-site mutation (IVS-2A > G), one deletion (976delG), and two non-sense mutations (Y140X and W314X). We found that missense mutation W547G also led to increased expression of a new alternative isoform lacking exons 10 and 11 that was expressed in several human tissues. In addition, we describe another novel CLCN5 splicing variant lacking exon 11 alone, which was expressed only in human skeletal muscle. We conclude that missense mutation W547G can also alter the expression levels of a CLCN5 mRNA splicing variant. This type of mutation has not been previously described in the CLCN5 gene. Our results support the importance of a routine analysis at the pre-mRNA level of mutations that are commonly assumed to cause single amino acids alterations.

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“…Dent's disease is a renal tubular disorder characterized by low-molecular-weight proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis, rickets, and eventual renal failure (OMIM: 300009; Lloyd et al 1996). This disease is caused by mutations in the CLCN5 gene that encodes the voltage-gated chloride channel ClC-5 (Fisher et al 1995;Lloyd et al 1996;Carballo-Trujillo et al 2003) although recent findings have shown that mutations in the OCRL1 gene, also involved in proximal tubular function, are responsible for the disease phenotype in some patients (Hoopes et al 2005). Studies with ClC-5 knockout mice showed that loss of ClC-5 function results in an endosomal acidification defect and reduced proximal tubular protein reabsorption, which explain the symptoms of Dent's disease (Piwon et al 2000).…”

Section: Introductionmentioning

confidence: 99%

The Alu insertion in the CLCN5 gene of a patient with Dent’s disease leads to exon 11 skipping

et al. 2005

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Alu sequences are short, interspersed elements that have generated more than one million copies in the human genome. They propagate by transcription followed by reverse transcription and integration, causing mutations, recombination, and changes in pre-mRNA splicing. We have recently identified a 345-bp long Alu Ya5 element inserted in codon 650 within exon 11 of the chloride channel ClC-5 gene (CLCN5) of a patient with Dent's disease. A microsatellite pedigree analysis indicated that the insertion occurred in the germline of the maternal grandfather. Dent's disease is an X-linked renal tubular disorder characterized by low-molecularweight proteinuria, hypercalciuria, nephrolithiasis, and nephrocalcinosis. Here, we found, by RT-PCR amplification of RNA extracted from the patient's blood and subsequent DNA sequencing, that the Alu insertion led to an aberrant splicing of the CLCN5 pre-mRNA that skipped exon 11. Using the ESE finder and RESCUE-ESE Web interfaces, we identified two high-score exonic splicing enhancer (ESE) sequences in the site of insertion. The functional significance of these ESE motifs is suggested by our observation that these sequences are highly conserved among mammal CLCN5 genes. Therefore, we suggest that the Alu insertion causes exon skipping by interfering with splicing regulatory elements.The altered splicing would predict a truncated ClC-5 protein that lacks critical domains for sorting and chloride channel function.

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Novel truncating mutations in the ClC-5 chloride channel gene in patients with Dent's disease

Abstract: Our study is the first to characterize mutations in the CLCN5 gene in Spanish patients with Dent's disease and expands the spectrum of CLCN5 mutations associated with this disease.

Cited by 31 publications

References 18 publications

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

A missense mutation in the chloride/proton ClC-5 antiporter gene results in increased expression of an alternative mRNA form that lacks exons 10 and 11. Identification of seven new CLCN5 mutations in patients with Dent’s disease

The Alu insertion in the CLCN5 gene of a patient with Dent’s disease leads to exon 11 skipping

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