Mutant channels contribute < 50% to Na+ current in paramyotonia congenita muscle

Nenad Mitrovic*, Alfred L. George, Reinhardt Rüdel, Frank Lehmann-Horn, Holger Lerche

*Corresponding author for this work

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

An important question dominantly inherited diseases, such as channelopathies, is the level of expression of the mutant protein, In our study, we address this issue by comparing the gating defects of two human muscle Na+ channel mutants (R1448C and R1448P) causing paramyotonia congenita in native muscle specimens from two patients with those of the same mutant recombinant channels expressed in human embryonic kidney (HEK-293) cells, Patch-clamp recordings of transfected HEK-293 cells revealed a pronounced slowing of the Na+ current decay, a left-shifted and decreased voltage dependence of steady-state inactivation, and an Increased frequency of channel reopenings for mutant compared with wild-type channels. For R1448P channels, inactivation was almost six-fold and for R1448C it was three-fold slower than for wild-type channels. The same defects, though less pronounced, as expected for a disorder with dominant inheritance, were observed for muscle specimens from paramyotonia congenita patients carrying these mutations. Quantitative kinetic analysis of Na+ channel inactivation in the paramyotonic muscle specimens separating wild-type from mutant channels suggested that no more than 38% of the channels in the paramyotonia congenita muscle specimen were of the mutant type. Our data raise the possibility that variability in the ratio of mutant to wild-type Na+ channels in the muscle membrane has an impact on the clinical severity of the phenotype.

Original languageEnglish (US)
Pages (from-to)1085-1092
Number of pages8
JournalBrain
Volume122
Issue number6
DOIs
StatePublished - Jun 1 1999

Keywords

  • Channelopathies
  • Human skeletal muscle
  • Inactivation
  • Na channel
  • Patch-clamp

ASJC Scopus subject areas

  • Clinical Neurology

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