© 2004 by European Society of Cardiology
Copyright © 2004, European Society of Cardiology
New KCNQ1 mutations leading to haploinsufficiency in a general population
Defective trafficking of a KvLQT1 mutant
aINSERM U582, Institut de Myologie, IFR no. 14, Groupe Hospitalier Pitié-Salpêtrière, 47 Boulevard de l'Hôpital, 75651 Paris Cedex 13, France
bINSERM U533, Laboratoire de Physiopathologie et de Pharmacologie Cellulaires et Moléculaires, Faculté de Médecine, Nantes, France
cINSERM U258, IFR no. 69, Villejuif, France
dService de Biochimie B, IFR no. 14, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Faculté de Pharmacie-Université Paris V, Paris, France
eService de Cardiologie, Groupe Hospitalier Lariboisière, Paris, France
*Corresponding author. Tel: +33-1-42-16-57-50; fax: +33-1-42-16-57-00. Email address: p.guicheney{at}myologie.chups.jussieu.fr
Objective: KCNQ1 mutations lead to the long QT syndrome (LQTS), characterized by a prolonged QT interval, syncopes and sudden death. However, some mutations are associated with non-penetrant phenotype (no symptoms, QTc normal or borderline). The objective of this study was to determine whether KCNQ1 variants are associated with borderline QTc prolongation in a general population and to evaluate the frequency of carriers. Methods: We selected 2008 unrelated and untreated healthy individuals from a non-patient population. The KCNQ1 gene was screened by denaturing high-performance liquid chromatography (dHPLC) in 50 men and 50 women presenting the longest QTc intervals (403 to 443 ms). Results: We identified a nonsense mutation, Y148X, and an in-frame deletion of the serine residue 276 (
S276), in S2 and S5 transmembrane domains, respectively. S276 KvLQT1 channels expressed in COS-7 cells failed to conduct any K+ current in the homozygous state. Besides, a slight reduction in channel activity was observed when coexpressed with WT KvLQT1 and IsK. Confocal microscopy performed on transfected COS-7 cells revealed that S276 KvLQT1 was retained in the endoplasmic reticulum, whereas WT KvLQT1 was localized in the cell membrane. The two mutation carriers presented borderline QTc interval prolongation at slow heart rate but a 24-h ECG recording revealed a marked QTc prolongation at higher heart rate for the Y148X carrier. Conclusions: In this population, two subjects with borderline QTc prolongations (438 and 443 ms) were carriers of KCNQ1 mutations leading to haploinsufficiency and are potentially at risk of developing drug-induced arrhythmia. The study provides the first demonstration of a defective cell surface localization of a KvLQT1 mutant missing one amino acid in a transmembrane domain.
KEYWORDS Ion channels; K-channel; Long QT syndrome
Abbreviations: D.E.S.I.R., Data from an Epidemiological Study on the Insulin Resistance Syndrome • dHPLC, denaturing high-performance liquid chromatography • DNA, deoxyribonucleic acid • ECG, electrocardiogram • JLNS, Jervell and Lange-Nielsen syndrome • LQTS, Long QT syndrome • PCR, polymerase chain reaction • QTc, QT interval corrected for heart rate with Fridericia formula (ms) • RWS, Romano-Ward syndrome
1 These authors contributed equally to the work.
Laetitia Gouas and Myriam Berthet performed the genetic analysis and identified the KCNQ1 mutations. Rachel Lescasse had worked on this project before leaving the laboratory U582. They were under the leadership of Dr. Pascale Guicheney. Françoise Simon was very helpful in introducing to the dHPLC technology under the leadership of Bernard Hainque. Chloe Bellocq performed the electrophysiological studies, Franck Potet performed the cellular localization of the S276 KvLQT1 mutant and Sophie Demolombe, the site-directed mutagenesis, under the leadership of Isabelle Baró. Anne Forhan and Beverley Balkau, from the D.E.S.I.R. study group, participated in the selection of the study population. Dr. Isabelle Denjoy organized a medical consultation for the two mutation carriers.
Time for primary review 23 days
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