MOLECULAR-GENETICS OF THE LONG QT SYNDROME - 2 NOVEL MUTATIONS OF THEKVLQT1 GENE AND PHENOTYPIC-EXPRESSION OF THE MUTANT-GENE IN A LARGE KINDRED

At least three different gene loci were recently shown to account for the long QT syndrome (LQTS), a monogenic disorder with altered myocard ial repolarization and occurrence of life threatening cardiac arrhythm ias, We screened 44 unrelated probands for mutations of the gene encod ing the cardiac potassium channel KVLQT1 using single-strand conformat ional polymorphism (SSCP) and subsequent DNA sequencing. Two different mutations, T182I and D188N, were identified in two separate pedigrees . Cosegregation of the mutation with the disease phenotype was evident in both families, No mutations were identified at codon 212, previous ly suggested to represent a mutational hot spot of the KVLQT1 channel, in any of the 44 probands. The large pedigree with the D188N mutation (30 affected and 43 nonaffected individuals) permitted an analysis of expression of the mutant gene in its documented carriers. Although th e mean (+/- SD) QTc interval was markedly longer in affected (484 +/- 38 ms) than in nonaffected individuals (406 +/- 27 ms, P < 0.001), the re was a marked overlapping of individual values in these two groups. QTc values in symptomatic and asymptomatic carriers of the mutant gene were not significantly different, In conclusion, we have identified t wo novel mutations of the KVLQT1 component of a cardiac potassium chan nel, Our data support the functional significance of the pore-S6 domai n of this membrane protein and emphasise the diagnostic usefulness of DNA analyses in families with LQTS. (C) 1998 Wiley-Liss, Inc.