title: Mutations in a dominant-negative isoform correlate with phenotype in inherited cardiac arrhythmias.
abstract: 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.
authors: Laboratoire de Physiopathologie et de Pharmacologie Cellulaires et Moléculaires, INSERM CJF96-01, Hôpital Hotel-Dieu, Nantes, France.
authors: R
authors: R
authors: Mohammad-Panah
authors: S
authors: S
authors: Demolombe
authors: N
authors: N
authors: Neyroud
authors: P
authors: P
authors: Guicheney
authors: F
authors: F
authors: Kyndt
authors: M
authors: M
authors: van den Hoff
authors: I
authors: I
authors: Baró
authors: D
authors: D
authors: Escande
mesh_terms: D000328:Adult; D017398:Alternative Splicing / Q000235:genetics; D000818:Animals; D019556:COS Cells; D002675:Child, Preschool; D005091:Exons / Q000235:genetics; D005260:Female; D015870:Gene Expression; D005799:Genes, Dominant / Q000235:genetics*; D005808:Genes, Recessive / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; D008133:Long QT Syndrome / Q000151:congenital* / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials; D010641:Phenotype; D011188:Potassium / Q000378:metabolism; D015221:Potassium Channels / Q000235:genetics* / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion / Q000235:genetics*; D013489:Suppression, Genetic / Q000235:genetics*; D014162:Transfection
chemical_list: D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D020033:Protein Isoforms; D011188:Potassium