Novel LQT-3 mutation affects Na+ channel activity through interactions between α- and β1-subunits

R. H. An, X. L. Wang, B. Kerem, J. Benhorin, A. Medina, M. Goldmit, R. S. Kass*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

172 Scopus citations

Abstract

The congenital long-QT syndrome (LQT), an inherited cardiac arrhythmia characterized in part by prolonged ventricular repolarization, has been linked to 5 loci, 4 of which have been shown to harbor genes that encode ion channels. Previously studied LQT-3 mutations of SCN5A (or hH1), the gene that encodes the human Na+ channel α-subunit, have been shown to encode voltage- gated Na+ channels that reopen during prolonged depolarization and hence directly contribute to the disease phenotype: delayed repolarization. Here, we report the functional consequences of a novel SCN5A mutation discovered in an extended LQT family. The mutation, a single A→G base substitution at nucleotide 5519 of the SCN5A cDNA, is expected to cause a nonconservative change from an aspartate to a glycine at position 1790 (D1790G) of the SCN5A gene product. We investigated ion channel activity in human embryonic kidney (HEK 293) cells transiently transfected with wild-type (hH1) or mutant (D1790G) cDNA alone or in combination with cDNA encoding the human Na+ channel β1-subunit (hβ1) using whole-cell patch-clamp procedures. Heteromeric channels formed by coexpression of α- and β1-subunits are affected: steady-state inactivation is shifted by -16 mV, but there is no D1790G-induced sustained inward current. This effect is independent of the β1-subunit isoform. We find no significant effect of D1790G on the biophysical properties of monomeric α- (hH1) channels. We conclude that the effects of the novel LQT-3 mutation on inactivation of heteromeric channels are due to D1790G-induced changes in α- and β1-interactions.

Original languageAmerican English
Pages (from-to)141-146
Number of pages6
JournalCirculation Research
Volume83
Issue number2
DOIs
StatePublished - 27 Jul 1998

Keywords

  • Genetics
  • Long-QT syndrome
  • Na channel

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