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

Congenital long QT syndrome (LQTS) is a heterogeneous group of heritabledisorders characterized by prolongation of the QT interval on theelectrocardiogram, ventricular arrhythmias and sudden death. At least fourgenes can, when mutated, produce this phenotype. Of these genes, therecently identified KVLQT1 potassium channel is thought to be the one mostcommonly responsible. In this study, we used single strand conformationalpolymorphism (SSCP) analysis to screen two large and nine small LQTSfamilies for mutations of the KVLQT1 potassium channel gene. We identifieda novel missense mutation in two unrelated families which substitutes aserine for a conserved glycine in the putative pore region of the KVLQT1channel. In a third family, a new alanine to valine mutation at a CpGdinucleotide resulted in the spontaneous occurrence of the long QT syndromein monozygotic twin offspring of unaffected parents. Mutations at this samenucleotide have been observed in eight of the 19 LQTS families determinedto have KVLQT1 mutations, suggesting this is a mutational hot spot. Both ofthese mutations alter the amino acid sequence in, or adjacent to, the poreof the channel and many diminish the channel's ability to conduct arepolarizing potassium current. To date, all KVLQT1 mutations determined tocause the LQTS are missense mutations. These data confirm the role ofKVLQT1 in the LQTS and suggest that mutant KVLQT1 proteins may exert adominant negative effect on repolarizing potassium currents by formingmultimers with normal potassium channel protein subunits, dramaticallyreducing the number of fully-functional KVLQT1 channels.