New Mutations in the KVLQT1 Potassium Channel That Cause Long-QT Syndrome

Abstract

Background-Long-QT syndrome (LQTS) is an inherited cardiac arrhythmia that causes sudden death in young, otherwise healthy people. Four genes for LQTS have been mapped to chromosome 11p15.5 (LQT1), 7q35-36 (LQT2), 3p21-24 (LQT3), and 4q25-27 (LQT4). Genes responsible for LQT1, LQT2, and LQT3 have been identified as cardiac potassium channel genes (KVLQT1, HERG) and the cardiac sodium channel gene (SCN5A). Methods and Results-After studying 115 families with LQTS, we used single-strand conformation polymorphism (SSCP) and DNA sequence analysis to identify mutations in the cardiac potassium channel gene, KVLQT1. Affected members of seven LQTS families were found to have new, previously unidentified mutations, including two identical missense mutations, four identical splicing mutations, and one 3-bp deletion. An identical splicing mutation was identified in affected members of four unrelated families (one Italian, one Irish, and two American), leading to an alternatively spliced form of KVLQT1. The 3-bp deletion arose de novo and occurs at an exon-intron boundary. This results in a single base deletion in the KVLQT1 cDNA sequence and alters splicing, leading to the truncation of KVLQT1 protein. Conclusions-We have identified LQTS-causing mutations of KVLQT1 in seven families. Five KVLQT1 mutations cause the truncation of KVLQT1 protein. These data further confirm that KVLQT1 mutations cause LQTS. The location and character of these mutations expand the types of mutation, confirm a mutational hot spot, and suggest that they act through a loss-of-function mechanism or a dominant-negative mechanism. (Circulation. 1998;97:1264-1269.)

Genomic Organization of the KCNQ1 K + Channel Gene and Identification of C-Terminal Mutations in the Long-QT Syndrome

“…The presence of mutations in the C-terminal domain, and even in the N-terminus, which has not been analyzed so far, may explain the low percentage of mutations identified in large LQTS cohorts. 25,30,33 In conclusion, this work provides helpful tools for linkage analysis and systematic mutation screening in the KCNQ1 gene.…”

“…The physiological role of isoforms 3, 4, and 5 remains enigmatic, whereas isoforms 1 and 2 associate with MinK to form a functional K ϩ channel in the heart underlying the I Ks current. 18,19 KCNQ1 mutations are numbered according to isoform 0 11,16,24,25 or to isoform 1. 6,17,21,26,27 The identification of the full-length exon 1a from genomic DNA suggests that a common nomenclature should be used for numbering KCNQ1 mutations according to isoform 1 sequence, which has been independently determined by two groups.…”

The genetic basis of long QT and short QT syndromes: A mutation update

“…Thus, for example, the p.A341V mutation, one of the most frequent causes of type 1 LQTS, was denoted p.A212V by Wang et al [1996b] and p.A246V by Li et al [1998]. LQTS-associated mutations in KCNQ1 are listed in Supp.…”

Impaired KCNQ1–KCNE1 and Phosphatidylinositol-4,5-Bisphosphate Interaction Underlies the Long QT Syndrome

“…1,2 Nearly 100 KCNQ1 mutations have been reported to cause the long QT syndrome, a genetic disease characterized by prolonged cardiac repolarization, cardiac arrhythmias, and a high risk of sudden death. 3,4 Phosphaditylinositol-4,5-bisphosphate (PIP 2 ) is an important intracellular regulator of many ion channels and transporters. [5][6][7][8] We showed recently that intracellular PIP 2 regulates KCNQ1-KCNE1 channel activity in such a way that PIP 2 stabilizes the open state of the channels, leading to an increased current amplitude, slowed deactivation kinetics, and a shift in the activation curve toward negative potentials.…”