Clinical and electrophysiological characterization of a novel mutation (F193L) in the KCNQ1 gene associated with long QT syndrome

Abstract

KCNQ1 is a gene encoding an α subunit of voltage-gated cardiac K+ channels, with properties similar to the slowly activating delayed rectifier K+ current, and one of the genes causing long QT syndrome (LQTS). However, genotype–phenotype correlations of the KCNQ1 gene mutations are not fully understood. The aims of this study were to identify a mutation in the KCNQ1 gene in patients with LQTS, and to characterize the clinical manifestations and electrophysiological properties of the mutation. We screened and identified mutations by PCR, single-strand conformational polymorphism analysis and DNA sequencing. We identified a novel mutation [Phe193Leu (F193L)] in the KCNQ1 gene in one family with LQTS. The patients with this mutation showed a mildly affected phenotype. The proband was a 17-year-old girl who had a prolonged QT interval. Her elder brother, father and paternal grandmother also had the mutation. None of them had any history of syncope. Sudden death was not found in this family. Next, we studied the electrophysiological characteristics of the F193L mutation in the KCNQ1 gene using the expression system in Xenopus oocytes and the two-microelectrode voltage-clamp technique. Co-expression of F193L KCNQ1 with the K+ channel minK suppressed peak (by 23.3%) and tail (by 38.2%) currents compared with those obtained by the combination of wild-type (WT) KCNQ1 and minK. Time constants of current activation in F193L KCNQ1 and F193L KCNQ1+minK were significantly slower than those of WT KCNQ1 and WT KCNQ1+minK. This electrophysiological study indicates that F193L causes less severe KCNQ1 current suppression, and thereby this mutation may result in a mildly affected phenotype.

Fatty acid analogue N-arachidonoyl taurine restores function of IKs channels with diverse long QT mutations

“…F193L does not alter the G ( V ), but speeds up K V 7.1+KCNE1 channel closing by a factor of 2 (Supplementary file 1). These results are consistent with previous reported findings for some of these mutants (Bianchi et al, 2000; Yamaguchi et al, 2003; Eldstrom et al, 2010; Henrion et al, 2009; Yang et al, 2013; Yang et al, 2002; Harmer et al, 2010). …”

“…We first study the biophysical properties of six point mutations in K V 7.1 (F193L, V215M, S225L, L251P, F351S, R583C), and two in KCNE1 (K70N, S74L) identified in patients with LQTS (Yamaguchi et al, 2003; Yang et al, 2002; Splawski et al, 1997; Priori et al, 1999; Napolitano et al, 2005; Lai et al, 2005) (Figure 1a). As L251P and F351S did not produce functional channels (Napolitano et al, 2005; Deschenes et al, 2003) (Figure 1—figure supplement 1), we engineered the milder L251A and F351A mutants instead.…”

“…We selected eight mutations of residues mutated in patients with LQTS located in different segments of the K V 7.1+KCNE1 channel and that were previously shown to form active channels (Bianchi et al, 2000; Yamaguchi et al, 2003; Eldstrom et al, 2010; Henrion et al, 2009; Yang et al, 2013; Yang et al, 2002; Harmer et al, 2010; Splawski et al, 1997). We measure the movement of the S4 voltage sensor in selected mutants using voltage clamp fluorometry to further our understanding of the molecular mechanisms underlying the defects caused by the diverse mutations.…”

Long QT syndrome and associated gene mutation carriers in Japanese children: results from ECG screening examinations

“…Mutations in various genes encoding cardiac ion channels and membrane adaptor proteins are known to cause this syndrome [2], and many LQTS mutations have been identified [3][4][5][6]. A previous study [7] has shown that approx.…”

Compound heterozygosity for mutations Asp611→Tyr in KCNQ1 and Asp609→Gly in KCNH2 associated with severe long QT syndrome

“…MinK and MiRP1 are known to form complexes with the KCNQ1 and KCNE2 channels, respectively, giving rise to the delayed potassium rectifier currents I Ks (slow component) and I Kr (rapid component). Although over 80 mutations in the KCNQ1 gene, including the F193L mutation observed previously by us [10], and over 90 mutations in the KCNH2 gene, including the M124T, R534 and E637K mutations observed by us [11][12][13], have been reported to date, the genotype-phenotype correlation is not completely understood. In addition, LQTS patients with double mutations in both the KCNQ1 and KCNH2 genes have not been reported to date.…”