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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

View larger version (15K): [in a new window]   Figure 1 Compound pedigree of families 041 and 090. Index family (referred to as 041090 in text) consists of subjects II/8, II/13, III/5, III/6 and III/7. Available corrected QT values (QTc, in ms) are shown under individual symbols. The medication may have affected the QTc values of subjects I/2 and I/4. In addition, subject II/3 has left bundle branch block in the electrocardiogram (ECG), which prolongs the QTc interval (values shown in parentheses). Neither the sample for DNA analysis nor the ECG was available from subjects marked by an asterisk. Open circles/squares = female/male mutation noncarriers; half-filled symbols = L552S heterozygotes; and filled symbols = L552S homozygotes.

View larger version (62K): [in a new window]   Figure 2 Electrocardiographic recordings (leads V1 to V6, paper speed 50 mm/s) of the index family. Subjects III/5 and III/6 (recordings at birth and three years of age while on propranolol) were subsequently shown to be homozygous for the L552S mutation.

View larger version (20K): [in a new window]   Figure 3 Distribution of corrected QT intervals (QTc, in ms) of L552S homozygotes, L552S heterozygotes (symptomatic shown as triangles and asymptomatic as circles) and L552S noncarriers. Only the QTc values of individuals with no medication are included.

View larger version (11K): [in a new window]   Figure 4 In vitro expression of the L552S mutation in COS7 cells. Whole-cell, patch-clamp recordings from a cell transfected with HERG-wt plasmid and with HERG-L552S plasmid. Note the rapid onset and rapid decay of the HERG-L552S currents. The common voltage protocol is shown on the right.