title: A double-point mutation in the selectivity filter site of the KCNQ1 potassium channel results in a severe phenotype, LQT1, of long QT syndrome.
abstract: BACKGROUND
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Cardiology, First Department of Internal Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: Taruna
authors.initials: T
authors.lastname: Ikrar
authors.forename: Haruo
authors.initials: H
authors.lastname: Hanawa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Watanabe
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Okada
authors.forename: Yoshiyasu
authors.initials: Y
authors.lastname: Aizawa
authors.forename: Mahmoud M
authors.initials: MM
authors.lastname: Ramadan
authors.forename: Satoru
authors.initials: S
authors.lastname: Komura
authors.forename: Fumio
authors.initials: F
authors.lastname: Yamashita
authors.forename: Masaomi
authors.initials: M
authors.lastname: Chinushi
authors.forename: Yoshifusa
authors.initials: Y
authors.lastname: Aizawa
mesh_terms: D000328:Adult; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000235:genetics*; D008133:Long QT Syndrome / Q000175:diagnosis* / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
chemical_list: D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human