Characterization of three myotonia-associated mutations of the CLCN1 chloride channel gene via heterologous expression.

Bronwyn J. Simpson, Tamara A. Height, Grigori Y. Rychkov, Kristen J. Nowak, Nigel G. Laing, Bernard P. Hughes, Allan H. Bretag

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Two novel mutations of the human CLCN1 chloride channel gene, c.592C>G (p.L198V) and c.2255A>G (p.K752R), are described, occurring coincidentally in the one myotonic patient. These individual mutations and a construct with both mutations in the one cDNA were transcribed and expressed in Xenopus oocytes where channel gating parameters were extracted from chloride currents recorded under voltage clamp. We found that the p.L198V mutation has its major effects on the common (or slow) gate of the chloride channel, as do other dominant ClC-1 mutations, and may therefore be causative of the patient's symptoms (when co-expressed with wild-type human ClC-1, the p.L198V mutation exerts a dominant negative effect on common gating) but the p.K752R mutation appears to be innocuous and may be a benign polymorphism. A third mutant, the recently described c.2795C>T (p.P932L), was expressed in HEK 293 cells. Despite the severity of the disease associated with this mutation, chloride currents in cells expressing p.P932L were not significantly different from those of cells expressing wild-type ClC-1.

Original languageEnglish
Pages (from-to)185
Number of pages1
JournalHuman mutation
Issue number2
Publication statusPublished or Issued - Aug 2004
Externally publishedYes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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