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CLINICAL STUDIES

Homozygosity for a HERG potassium channel mutation causes a severe form of long QT syndrome: identification of an apparent founder mutation in the Finns

Kirsi Piippo, PhD^*, P.äivi Laitinen, PhD^*, Heikki Swan, MD^*, Lauri Toivonen, MD^*, Matti Viitasalo, MD^*, Michael Pasternack, PhD, Kristian Paavonen, MD^*, Hugh Chapman, PhD , Kenneth T. Wann, PhD, Eeva Hirvelä, MD, Antti Sajantila, MD and Kimmo Kontula, MD^*

^* Department of Medicine, University of Helsinki, Helsinki, Finland
Institute of Biotechnology and Department of Pharmacy, Division of Pharmacology and Toxicology, University of Helsinki, Helsinki, Finland
School of Pharmacy, University of Cardiff, Wales, United Kingdom
Department of Forensic Medicine, University of Helsinki, Helsinki, Finland

Manuscript received July 6, 1999; revised manuscript received December 13, 1999, accepted February 9, 2000.

Reprint requests and correspondence: Prof. Kimmo Kontula, University of Helsinki, Department of Medicine, Haartmaninkatu 4, 00290 Helsinki, Finland
kimmo.kontula{at}hus.fi

OBJECTIVES

We studied the clinical characteristics and molecular background underlying a severe phenotype of long QT syndrome (LQTS).

BACKGROUND

Mutations of cardiac ion channel genes cause LQTS, manifesting as increased risk of ventricular tachycardia and sudden death.

METHODS

We studied two siblings showing prolonged QT intervals corrected for heart rate (QTc), their asymptomatic parents with only marginally prolonged QTc intervals and their family members. The potassium channel gene HERG was screened for mutations by deoxyribonucleic acid sequencing, and the electrophysiologic consequences of the mutation were studied in vitro using the whole-cell patch-clamp technique.

RESULTS

A novel missense mutation (L552S) in the HERG channel, present in the homozygous state in the affected siblings and in the heterozygous state in their parents, as well as in 38 additional subjects from six LQTS families, was identified. One of the homozygous siblings had 2:1 atrioventricular block immediately after birth, and died at the age of four years after experiencing unexplained hypoglycemia. The other sibling had an episode of torsade de pointes at the age of two years. The mean QTc interval differed significantly (p < 0.001) between heterozygous symptomatic mutation carriers (500 ± 59 ms), asymptomatic mutation carriers (452 ± 34 ms) and noncarriers (412 ± 23 ms). When expressed in vitro, the HERG-L552S formed functional channels with increased activation and deactivation rates.

CONCLUSIONS

Our data demonstrate that homozygosity for a HERG mutation can cause a severe cardiac repolarization disorder without other phenotypic abnormalities. Absence of functional HERG channels appears to be one cause for intrauterine and neonatal bradycardia and 2:1 atrioventricular block.

Abbreviations and Acronyms   DNA = deoxyribonucleic acid   EAD = early afterdepolarization   IKr = rapidly activated delayed rectifier potassium channel   IKs = slowly activated delayed rectifier potassium channel   LQTS = long QT syndrome   LQT2 = type 2 long QT syndrome   PCR = polymerase chain reaction   PIRA = primer-induced restriction assay   QTc = QT interval corrected for heart rate

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