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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

View larger version (28K): [in a new window]   Figure 1 Pedigrees of families 1012 and 1034. Squares represent males, circles are females and symbols with slash mark represent deceased subjects. Half-filled symbols indicate heterozygous KCNQ1-Fin carriers, filled symbols homozygous KCNQ1-Fin carriers and half-striped symbols are heterozygous Y171X carriers. Open symbols denote unaffected individuals verified by deoxyribonucleic acid (DNA) assay. Subjects IV/6 and IV/8 in family 1012 and III/7 in family 1034 have Jervell and Lange-Nielsen syndrome (JLNS). The QTc interval (ms) is shown under each symbol; those marked with an asterisk have been recorded during medication.

View larger version (24K): [in a new window]   Figure 2 In vitro expression of the KCNQ1-Fin mutation in COS cells. (a) Whole-cell patch-clamp recordings from cells transfected with KCNQ1-wt + minK; (b) KCNQ1-wt + KCNQ1-Fin + minK; and (c) KCNQ1-Fin + minK. The relative activation curves obtained from the immediate tail are plotted in (d). The common voltage protocol used in these experiments is shown in (e).

View larger version (42K): [in a new window]   Figure 3 Number of established male (hatched bars) and female (open bars) KCNQ1-Fin carriers according to their QTc interval classes, and percentage of symptomatic individuals in the same classes (males and females combined). None of the individuals included in this analysis had any medication at the moment of QTc measurement. QTc = QT interval corrected for heart rate according to Bazett’s formula.

View larger version (22K): [in a new window]   Figure 4 Geographical distribution of ancestral KCNQ1-Fin carriers. Each spot on the map represents the earliest recognized KCNQ1-Fin carrier of the affected family (n = 34). The early immigration probably took place from the east and the late immigration from the south and west. A major internal movement started in the sixteenth century from southeastern Finland toward the western and northern parts of the country.