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

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 SerdarogluM. Andrew Nesbit, Frances Ashcroft, Rajesh V. Thakker

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23 Citations (Scopus)

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.

Original languageEnglish
JournalNephron - Physiology
Volume112
Issue number4
DOIs
Publication statusPublished - Jun 2009
Externally publishedYes

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Keywords

  • CLC-4
  • CLC-5
  • Cofilin
  • Dent's disease
  • Mutations
  • OCRL1

ASJC Scopus subject areas

  • Medicine(all)
  • Physiology
  • Nephrology
  • Physiology (medical)

Cite this

Wu, F., Reed, A. A. C., Williams, S. E., Loh, N. Y., Lippiat, J. D., Christie, P. T., Large, O., Bettinelli, A., Dillon, M. J., Goldraich, N. P., Hoppe, B., Lhotta, K., Loirat, C., Malik, R., Morel, D., Kotanko, P., Roussel, B., Rubinger, D., Schrander-Stumpel, C., ... Thakker, R. V. (2009). Mutational analysis of CLC-5, cofilin and CLC-4 in patients with dent's disease. Nephron - Physiology, 112(4). https://doi.org/10.1159/000225944