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

Am J Hum Genet. 1999 Apr;64(4):1015-23. doi: 10.1086/302346.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Alternative Splicing / genetics
  • Animals
  • COS Cells
  • Child, Preschool
  • Exons / genetics
  • Female
  • Gene Expression
  • Genes, Dominant / genetics*
  • Genes, Recessive / genetics
  • Heterozygote
  • Humans
  • KCNQ Potassium Channels
  • KCNQ1 Potassium Channel
  • Long QT Syndrome / congenital*
  • Long QT Syndrome / genetics*
  • Long QT Syndrome / metabolism
  • Male
  • Membrane Potentials
  • Phenotype
  • Potassium / metabolism
  • Potassium Channels / genetics*
  • Potassium Channels / metabolism
  • Potassium Channels, Voltage-Gated*
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Sequence Deletion / genetics*
  • Suppression, Genetic / genetics*
  • Transfection


  • KCNQ Potassium Channels
  • KCNQ1 Potassium Channel
  • KCNQ1 protein, human
  • Potassium Channels
  • Potassium Channels, Voltage-Gated
  • Protein Isoforms
  • Potassium