NOVEL DONOR SPLICE-SITE MUTATION IN THE KVLQT1 GENE IS ASSOCIATED WITH LONG QT SYNDROME

KVLQT1 Gene Mutation and LQTS, Introduction: Inherited long QT syndrom e (LQTS) recently has been associated with mutations in genes coding f or potassium (KVLQTI, KCNE1, and HERG) or sodium (SCN5A) ion channels involved in regulating either sodium inward or potassium outward curre nts of heart cells, resulting in prolongation of the repolarization pe riod. We describe a new mutation, a -1 donor splice site mutation in a kindred with two affected members (QTc = 0.61 and 0.54 sec). Methods and Results: Single stranded conformation polymorphism (SSCP) analyses were performed on DNA fragments amplified by polymerase chain reactio n from DNA extracted from whole blood. Aberrant conformers were analyz ed by DNA sequencing. SSCP analysis of the KVLQT1 gene revealed an abe rrant conformer in the affected family members. DNA sequencing confirm ed the presence of a G-->A change in the last nucleotide of codon 344. This mutation does not cause an amino acid change, but a change of th e splice site characteristics at the 3' end of exon 6. The mutation ma y affect, through deficient splicing, the putative sixth transmembrane segment of the K+ channel, and this type of mutation has not previous ly been described in KVLQT1. Conclusion: The clinical course of LQTS i n the affected family members, in whom no deaths occurred despite 20 t o 30 syncopes, can be explained by the ability of the cellular machine ry to perform partial correct splicing in the mutant allele. This type of mutation may be misinterpreted as a normal variant, since it is a point mutation causing neither an amino acid change nor the introducti on of a stop codon.