TY - JOUR
T1 - Novel LQT-3 mutation affects Na+ channel activity through interactions between α- and β1-subunits
AU - An, R. H.
AU - Wang, X. L.
AU - Kerem, B.
AU - Benhorin, J.
AU - Medina, A.
AU - Goldmit, M.
AU - Kass, R. S.
PY - 1998/7/27
Y1 - 1998/7/27
N2 - 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.
AB - 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.
KW - Genetics
KW - Long-QT syndrome
KW - Na channel
UR - http://www.scopus.com/inward/record.url?scp=0032572594&partnerID=8YFLogxK
U2 - 10.1161/01.RES.83.2.141
DO - 10.1161/01.RES.83.2.141
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C2 - 9686753
AN - SCOPUS:0032572594
SN - 0009-7330
VL - 83
SP - 141
EP - 146
JO - Circulation Research
JF - Circulation Research
IS - 2
ER -