A double-point mutation in the selectivity filter site of the KCNQ1 potassium channel results in a severe phenotype, LQT1, of long QT syndrome

J Cardiovasc Electrophysiol. 2008 May;19(5):541-9. doi: 10.1111/j.1540-8167.2007.01076.x. Epub 2008 Feb 4.


Introduction: Slowly activating delayed-rectifier potassium currents in the heart are produced by a complex protein with alpha and beta subunits composed of the potassium voltage-gated channel KQT-like subfamily, member 1 (KCNQ1) and the potassium voltage-gated channel Isk-related family, member 1 (KCNE1), respectively. Mutations in KCNQ1 underlie the most common type of hereditary long QT syndrome (LQTS). Like other potassium channels, KCNQ1 has six transmembrane domains and a highly conserved potassium selectivity filter in the pore helix called "the signature sequence." We aimed to investigate the functional consequences of a newly identified mutation within the signature sequence.

Methods and results: Potassium channel genomic DNA from a family with clinical evidence of LQTS was amplified by polymerase chain reaction (PCR), and the resulting products were then sequenced. Three family members had a double-point mutation in KCNQ1 at nucleotides 938 (T-to-A) and 939 (C-to-A), resulting in an isoleucine-to-lysine change at amino acid position 313. These patients displayed prolonged QTc intervals (629, 508, and 500 ms(1/2,) respectively) and repetitive episodes of syncope, but no deafness. Three-dimensional structure modeling of KCNQ1 revealed that this mutation is located at the center of the channel pore. COS-7 cells displayed a lack of current when transfected with a plasmid expressing the mutant. In addition, the mutant displayed a dominant negative effect on current but appeared normal with respect to plasma membrane integration.

Conclusion: An I313K mutation within the selectivity filter of KCNQ1 results in a dominant-negative loss of channel function, leading to a long QT interval and subsequent syncope.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Female
  • Genetic Predisposition to Disease / genetics
  • Heterozygote
  • Humans
  • KCNQ1 Potassium Channel / genetics*
  • Long QT Syndrome / diagnosis*
  • Long QT Syndrome / genetics*
  • Middle Aged
  • Mutation / genetics
  • Phenotype
  • Polymorphism, Single Nucleotide / genetics*


  • KCNQ1 Potassium Channel
  • KCNQ1 protein, human