Dominant-negative isoforms modulate phenotype in inherited cardiac arrhythmias

Abstract

Romano-Ward syndrome (RWS) is a dominantly inherited cause of cardiac arrhythmias that can lead to syncope and sudden death. It results from mutations in the KCNQ1 gene; mutations in this gene also cause Jervell and Lange-Nielsen syndrome (JLN), an autosomal recessive condition that is characterized by cardiac arrhythmias and congenital deafness. KCNQ1 encodes the pore-forming K+ ion channel subunit, KvLQT1. Together with its β-subunit, IsK, KvLQT1 produces the slow component of the delayed rectifier K+ current in the heart. RWS and JLN mutations reduce this current, prolonging repolarization and predisposing to abnormalities in cardiac rhythm.When expressed in vitro, RWS and JLN mutations are indistinguishable, leading to the absence or significant reduction of the K+ current. So how can the very different phenotypic consequences in heterozygous carriers be explained? An N-terminal, truncated splice variant of KvLQT1, isoform 2, that is constitutively expressed in the heart is known to exert a dominant-negative effect on full-length KvLQT1 protein (isoform 1). All RWS and JLN mutations are common to both isoforms. In this paper1xMutations in a dominant-negative isoform correlate with phenotype in inherited cardiac arrhythmias. Mohammad-Panah, R. et al. Am. J. Hum. Genet. 1999; 64: 1015–1023Abstract | Full Text | Full Text PDF | PubMed | Scopus (59)See all References1, the effects of six mutations on isoform 2 are examined by functional expression in COS-7 cells and by measuring the K+ current generated. With the three RWS mutations, isoform 2 retained significant dominant-negative activity whereas this was abolished by the three JLN mutations. The authors propose a mechanism whereby in JLN heterozygotes, both isoforms produced from the mutant allele are inactive. However, as the wild-type KvLQT1 isoforms function normally there is little or no deleterious effect from the reduction in dosage. In RWS heterozygotes, isoform 1 is inactivated but mutant isoform 2 retains its dominant-negative effect and can exert this upon wild-type isoform 1. The resulting imbalance downregulates KvLQT1 function significantly below the level seen in JLN heterozygotes, thus producing a dominant phenotype. This complex interplay between isoforms has not previously been implicated in modulating genetic disease, but several other genes have dominant-negative isoforms and the possibility that a similar mechanism could be operating in other conditions is intriguing.