CLINICAL STUDY: ELECTROPHYSIOLOGY
A founder mutation of the potassium channel KCNQ1 in long QT syndrome
Implications for estimation of disease prevalence and molecular diagnostics
Kirsi Piippo, MSc*,
Heikki Swan, MD*,
Michael Pasternack, PhD ,
Hugh Chapman, PhD,
Kristian Paavonen, MD*,
Matti Viitasalo, MD*,
Lauri Toivonen, MD* and
Kimmo Kontula, MD*
* Department of Medicine, University of Helsinki, Helsinki, Finland
Institute of Biotechnology, University of Helsinki, Helsinki, Finland
Manuscript received May 23, 2000;
revised manuscript received August 23, 2000,
accepted October 4, 2000.
Reprint requests and correspondence: Professor Kimmo Kontula, University of Helsinki, Department of Medicine, Haartmaninkatu 4, FIN-00290 Helsinki, Finland
kimmo.kontula{at}hus.fi
OBJECTIVES
We took advantage of the genetic isolate of Finns to characterize a common long QT syndrome (LQTS) mutation, and to estimate the prevalence of LQTS.
BACKGROUND
The LQTS is caused by mutations in different ion channel genes, which vary in their molecular nature from family to family.
METHODS
The potassium channel gene KCNQ1 was sequenced in two unrelated Finnish patients with Jervell and Lange-Nielsen syndrome (JLNS), followed by genotyping of 114 LQTS probands and their available family members. The functional properties of the mutation were studied using a whole-cell patch-clamp technique.
RESULTS
We identified a novel missense mutation (G589D or KCNQ1-Fin) in the C-terminus of the KCNQ1 subunit. The voltage threshold of activation for the KCNQ1-Fin channel was markedly increased compared to the wild-type channel. This mutation was present in homozygous form in two siblings with JLNS, and in heterozygous form in 34 of 114 probands with Romano-Ward syndrome (RWS) and 282 family members. The mean (± SD) rate-corrected QT intervals of the heterozygous subjects (n = 316) and noncarriers (n = 423) were 460 ± 40 ms and 410 ± 20 ms (p < 0.001), respectively.
CONCLUSIONS
A single missense mutation of the KCNQ1 gene accounts for 30% of Finnish cases with LQTS, and it may be associated with both the RWS and JLNS phenotypes of the syndrome. The relative enrichment of this mutation most likely represents a founder gene effect. These circumstances provide an excellent opportunity to examine how genetic and nongenetic factors modify the LQTS phenotype.
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Abbreviations and Acronyms
| | DNA | = deoxyribonucleic acid | | ECG | = electrocardiogram/electrocardiographic | | JLNS | = Jervell and Lange-Nielsen syndrome | | LCSD | = left cardiac sympathetic denervation | | LQTS | = long QT syndrome | | LQT1 | = LQT1 type of long QT syndrome | | PCR | = polymerase chain reaction | | QTc | = QT interval corrected for heart rate with Bazett’s formula (ms) | | RWS | = Romano-Ward syndrome | | SIDS | = sudden infant death syndrome |
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