KVLQT1 mutations in three families with familial or sporadic long QT syndrome

Congenital long QT syndrome (LQTS) is a heterogen-eous group of heritable disorders characterized by prolongation of the QT interval on the electrocardio-gram, ventricular arrhythmias and sudden death. At least four genes can, when mutated, produce this phe-notype. Of these genes, the recently identified KVLQT1 potassium channel is thought to be the one most com-monly responsible. In this study, we used single strand conformational polymorphism (SSCP) analysis to screen two large and nine small LQTS families for mutations of the KVLQT1 potassium channel gene. We identified a novel missense mutation in two unrelated families which substitutes a serine for a conserved gly-cine in the putative pore region of the KVLQT1 channel. In a third family, a new alanine to valine mutation at a CpG dinucleotide resulted in the spontaneous occur-rence of the long QT syndrome in monozygotic twin offspring of unaffected parents. Mutations at this same nucleotide have been observed in eight of the 19 LQTS families determined to have KVLQT1 mutations, suggesting this is a mutational hot spot. Both of these mutations alter the amino acid sequence in, or adjac-ent to, the pore of the channel and may diminish the channel’s ability to conduct a repolarizing potassium current. To date, all KVLQT1 mutations determined to cause the LQTS are missense mutations. These data confirm the role of KVLQT1 in the LQTS and suggest that mutant KVLQT1 proteins may exert a dominant negative effect on repolarizing potassium currents by forming multimers with normal potassium channel protein subunits, dramatically reducing the number of fully-functional KVLQT1 channels