An intronic mutation leading to incomplete skipping of exon-2 in KCNQ1 rescues hearing in Jervell and Lange-Nielsen syndrome

Prog Biophys Mol Biol. Oct-Nov 2008;98(2-3):319-27. doi: 10.1016/j.pbiomolbio.2008.10.004. Epub 2008 Nov 5.


Romano-Ward syndrome (RWs) and Jervell and Lange-Nielsen Syndrome (JLNs) are two inherited arrhythmia disorders caused by monoallelic or bi-allelic mutations, respectively, in the KCNQ1 or KCNE1 genes. Both disorders could cause Long QT syndrome either without deafness (RWs), or with deafness (JLNs). We have performed clinical, molecular and functional investigation in two consanguineous Arabian families with history of sudden death of several children. Importantly, none of the affected individuals had (or have) any hearing impairment. Homozygosity mapping followed by molecular analysis identified a novel splice acceptor site mutation (homozygously) in intron-1 of the KCNQ1 gene (c.387 -5T>A), in these two apparently unlinked families. RNA analysis revealed that this splice site mutation causes incomplete transcriptional aberration of the KCNQ1 gene, leaving 10% of the normal allele transcript intact, which restores the hearing function. Our molecular and functional data provide the first evidence that small amount (as low as 10%) of normal KCNQ1 current can effectively maintain the hearing function but fails to maintain cardiac repolarization characteristics within normal limits. Additionally, we have revealed four extra low frequency aberrant isoforms emphasizing the importance of intronic and other non-coding sequences in maintaining cellular homeostasis as pathologic changes in a single nucleotide can affect splicing events at distant sites. The novel KCNQ1 mutation found in this study is very likely a founder mutation in the southern province of Saudi Arabia emphasizing its screening in the LQT population in this region.

MeSH terms

  • Adolescent
  • Base Sequence
  • Child, Preschool
  • Consanguinity
  • DNA, Complementary / genetics
  • Deafness / genetics*
  • Electrocardiography
  • Exons
  • Female
  • Founder Effect
  • Homozygote
  • Humans
  • Introns
  • Jervell-Lange Nielsen Syndrome / genetics*
  • Jervell-Lange Nielsen Syndrome / physiopathology
  • KCNQ1 Potassium Channel / genetics*
  • Male
  • Mutation
  • Pedigree
  • Saudi Arabia


  • DNA, Complementary
  • KCNQ1 Potassium Channel
  • KCNQ1 protein, human