Medical and Biomedical Researches

A KCNQ1 V205M missense mutation causes a high rate of long QT syndrome in a First Nations community

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.

PURPOSE:: 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. CONCLUSION:: 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.

Arbour L, Rezazadeh S, Eldstrom J, Weget-Simms G, Rupps R, Dyer Z, Tibbits G, Accili E, Casey B, Kmetic A, Sanatani S, Fedida D.

From the 1Departments of Medical Genetics, and 2Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, British Columbia; 3School of Kinesiology, Simon Fraser University, Burnaby, British Columbia; 4Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia; 5Department of Pathology, University of British Columbia, Vancouver, British Columbia; 6Department of Human and Social Development, University of Victoria, Victoria, British Columbia; and 7Division of Pediatric Cardiology, Department of Pediatrics, University of British Columbia, British Columbia Children’s Hospital, Vancouver, British Columbia, Canada.