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Article Dans Une Revue American Journal of Human Genetics Année : 1999

Mutations in a Dominant-Negative Isoform Correlate with Phenotype in Inherited Cardiac Arrhythmias

Résumé

The long QT syndrome is characterized by prolonged cardiac repolarization and a high risk of sudden death. Mutations in the KCNQ1 gene, which encodes the cardiac KvLQT1 potassium ion (K+) channel, cause both the autosomal dominant Romano-Ward (RW) syndrome and the recessive Jervell and Lange-Nielsen (JLN) syndrome. JLN presents with cardiac arrhythmias and congenital deafness, and heterozygous carriers of JLN mutations exhibit a very mild cardiac phenotype. Despite the phenotypic differences between heterozygotes with RW and those with JLN mutations, both classes of variant protein fail to produce K+ currents in cultured cells. We have shown that an N-terminus-truncated 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 investigated 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 suppress the dominant-negative effects of the truncated KvLQT1. Thus, in JLN heterozygous carriers, the full-length KvLQT1 protein encoded by the unaffected allele should not be subject to the negative influence of the mutated truncated isoform, leaving some cardiac K+ current available for repolarization. This is the first report of a genetic disease in which the impact of a mutation on a dominant-negative isoform correlates with the phenotype.

Dates et versions

hal-02330661 , version 1 (24-10-2019)

Identifiants

Citer

Raha Mohammad-Panah, Sophie Demolombe, Nathalie Neyroud, Pascale Guicheney, Florence Kyndt, et al.. Mutations in a Dominant-Negative Isoform Correlate with Phenotype in Inherited Cardiac Arrhythmias. American Journal of Human Genetics, 1999, 64 (4), pp.1015-1023. ⟨10.1086/302346⟩. ⟨hal-02330661⟩
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