title: A KCNQ1 V205M missense mutation causes a high rate of long QT syndrome in a First Nations community of northern British Columbia: a community-based approach to understanding the impact.
abstract: OBJECTIVE
  Hereditary long QT syndrome is named for a prolonged QT interval reflecting predisposition to ventricular arrhythmias and sudden death. A high rate in a remote, northern Canadian First Nations community was brought to attention.
  
  
  METHODS
  Two severely affected index cases and 122 relatives were ascertained using community-based participatory research principles. Genetic sequencing of five known genes responsible for long QT syndrome was carried out on the index cases, leading to the identification of a novel missense mutation. Functional properties of the identified mutation were studied in transfected mouse ltk- cells using whole cell patch clamp techniques. Corrected QT interval measurements were obtained from participants and subsequent genotyping of relatives was carried out.
  
  
  RESULTS
  In the two index cases, a novel missense mutation (V205M) was identified in the S3 transmembrane helix of KvLQT1, the pore forming domain of the IKs channel complex. In transfected mouse ltk-cells the V205M mutation suppressed IKs by causing a dramatic depolarizing shift in activation voltage coupled with acceleration of channel deactivation. Twenty-two mutation carriers had a significantly higher mean corrected QT interval than noncarriers (465 +/- 28 milliseconds vs. 434 +/- 26 milliseconds, P < 0.0001); however, 30% of carriers had a corrected QT interval below 440 milliseconds.
  
  
  CONCLUSIONS
  A novel KCNQ1 mutation in this founder population likely confers increased susceptibility to arrhythmias because of decreased IKs current. Even with a common mutation within a relatively homogenous population, clinical expression remains variable, exemplifying the multifactorial nature of long QT syndrome, and supporting the difficulty of definitive diagnosis without genetic testing. A community participatory approach enabled a comprehensive evaluation of the impact.
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada. larbour@uvic.ca
authors.forename: Laura
authors.initials: L
authors.lastname: Arbour
authors.forename: Saman
authors.initials: S
authors.lastname: Rezazadeh
authors.forename: Jodene
authors.initials: J
authors.lastname: Eldstrom
authors.forename: Gwen
authors.initials: G
authors.lastname: Weget-Simms
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Rupps
authors.forename: Zoe
authors.initials: Z
authors.lastname: Dyer
authors.forename: Glen
authors.initials: G
authors.lastname: Tibbits
authors.forename: Eric
authors.initials: E
authors.lastname: Accili
authors.forename: Brett
authors.initials: B
authors.lastname: Casey
authors.forename: Andrew
authors.initials: A
authors.lastname: Kmetic
authors.forename: Shubhayan
authors.initials: S
authors.lastname: Sanatani
authors.forename: David
authors.initials: D
authors.lastname: Fedida
mesh_terms: D000818:Animals; D001955:British Columbia / Q000453:epidemiology; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D007198:Indians, North American / Q000208:ethnology / Q000235:genetics*; D051657:KCNQ1 Potassium Channel / Q000235:genetics* / Q000378:metabolism; D008133:Long QT Syndrome / Q000453:epidemiology* / Q000208:ethnology / Q000235:genetics*; D051379:Mice; D020125:Mutation, Missense / Q000235:genetics*; D018408:Patch-Clamp Techniques; D010375:Pedigree; D017422:Sequence Analysis, DNA
chemical_list: D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human