Mutations in a dominant-negative isoform correlate with phenotype in inherited cardiac arrhythmias

The long QT syndrome is characterized by prolonged cardiac repolarization a nd a high risk of sudden death. Mutations in the KCNQ1 gene, which encodes the cardiac KvLQT1 potassium ion (KC) channel, cause both the autosomal dom inant Romano-Ward (RW) syndrome and the recessive Jervell and Lange-Nielsen (JLN) syndrome. JLN presents with cardiac arrhythmias and congenital deafn ess, and heterozygous carriers of JLN mutations exhibit a very mild cardiac phenotype. Despite the phenotypic differences between heterozygotes with R W and those with JLN mutations, both classes of variant protein fail to pro duce K+ currents in cultured cells. We have shown that an N-terminus-trunca ted KvLQT1 isoform endogenously expressed in the human heart exerts strong dominant-negative effects on the full-length KvLQT1 protein. Because RW and JLN mutations concern both truncated and full-length KvLQT1 isoforms, we i nvestigated whether RW or JLN mutations would have different impacts on the dominant-negative properties of the truncated KvLQT1 splice variant. In a mammalian expression system, we found that JLN, but not RW, mutations suppr ess the dominant-negative effects of the truncated KvLQT1. Thus, in JLN het erozygous carriers, the full-length KvLQT1 protein encoded by the unaffecte d allele should not be subject to the negative influence of the mutated tru ncated isoform, leaving some cardiac K+ current available for repolarizatio n. This is the first report of a genetic disease in which the impact of a m utation on a dominant-negative isoform correlates with the phenotype.