Mutational analysis of CLC-5, cofilin and CLC-4 in patients with Dent's disease.

Abstract

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.

• Authors: Fiona Wu, Anita A C Reed, Sian E Williams, Nellie Y Loh, Jonathan D Lippiat, Paul T Christie, Oliver Large, Alberto Bettinelli, Michael J Dillon, Noemia P Goldraich, Bernd Hoppe, Karl Lhotta, Chantal Loirat, Rayaz Malik, Delphine Morel, Peter Kotanko, Bernard Roussel, Dvora Rubinger, Connie Schrander-Stumpel, Erkin Serdaroglu, M Andrew Nesbit, Frances Ashcroft, Rajesh V Thakker
• Journal: Nephron. Physiology (Nephron Physiol) Vol. 112 Issue 4 Pg. p53-62 ( 2009) ISSN: 1660-2137 [Electronic] Switzerland
• PMID: 19546591 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2009 S. Karger AG, Basel.

Chemical References

• CFL1 protein, human
• CLC-5 chloride channel
• CLCN4 protein, human
• Chloride Channels
• Codon, Nonsense
• Cofilin 1
• Calcium

Topics

• Amino Acid Sequence
• Base Sequence
• Calcium (administration & dosage, pharmacokinetics, urine)
• Cell Line
• Chloride Channels (genetics, physiology)
• Codon, Nonsense
• Cofilin 1 (genetics)
• DNA Mutational Analysis
• Electrophysiology
• Female
• Genetic Diseases, X-Linked (genetics, physiopathology)
• Humans
• Kidney Diseases (genetics, physiopathology)
• Male
• Mutagenesis, Insertional
• Mutation
• Mutation, Missense
• Pedigree
• Sequence Deletion
• Transfection