GENOMIC ORGANIZATION AND MUTATIONAL ANALYSIS OF KVLQT1, A GENE RESPONSIBLE FOR FAMILIAL LONG QT SYNDROME

To elucidate the role of the KVLQT1 gene in the pathogenesis of long Q T syndrome (LQTS), we have established a screening system for detectin g KVLQT1 mutations by the polymerase chain reaction-single strand conf ormation polymorphism technique (PCR-SSCP). We first determined exon/i ntron boundaries and flanking intronic sequences, and found that the K VLQT1 gene consists of 17 coding exons. Subsequently, we synthesized o ligonucleotide primers to cover the coding region and the flanking int ronic sequences, and searched for mutations in 31 Japanese LOTS famili es. When genomic DNA from each proband was examined by PCR-SSCP follow ed by direct DNA sequencing, mutations were detected in five families; two independent families carried the same mutation and three of the f our were novel. Each mutation was present in affected relatives of the respective proband. This work will enable us to search more thoroughl y or LOTS mutations associated with KVLQT1, anti eventually will help us in finding genotype/phenotype relationships.