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. 2002 Sep;71(3):663-8.
doi: 10.1086/342360. Epub 2002 Jul 29.

KCNJ2 mutation results in Andersen syndrome with sex-specific cardiac and skeletal muscle phenotypes

Gregor Andelfinger  1 , Andrew R Tapper, Richard C Welch, Carlos G Vanoye, Alfred L George Jr, D Woodrow Benson
Affiliations

KCNJ2 mutation results in Andersen syndrome with sex-specific cardiac and skeletal muscle phenotypes

Gregor Andelfinger et al. Am J Hum Genet. 2002 Sep.

Abstract

Evaluation of candidate loci culminated in the identification of a heterozygous missense mutation (R67W) in KCNJ2, the gene encoding the inward-rectifying potassium current, Kir2.1, in 41 members of a kindred in which ventricular arrhythmias (13 of 16 female members [81%]) and periodic paralysis (10 of 25 male members [40%]) segregated as autosomal dominant traits with sex-specific variable expressivity. Some mutation carriers exhibited dysmorphic features, including hypertelorism, small mandible, syndactyly, clinodactyly, cleft palate, and scoliosis, which, together with cardiodysrhythmic periodic paralysis, have been termed "Andersen syndrome." However, no individual exhibited all manifestations of Andersen syndrome, and this diagnosis was not considered in the proband until other family members were examined. Other features seen in this kindred included unilateral dysplastic kidney and cardiovascular malformation (i.e., bicuspid aortic valve, bicuspid aortic valve with coarctation of the aorta, or valvular pulmonary stenosis), which have not been previously associated. Nonspecific electrocardiographic abnormalities were identified in some individuals, but none had a prolonged QT interval. Biophysical characterization of R67W demonstrated loss of function and a dominant-negative effect on Kir2.1 current. These findings support the suggestion that, in addition to its recognized role in function of cardiac and skeletal muscle, KCNJ2 plays an important role in developmental signaling.

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Figures

Figure 1
Figure 1
Electrocardiogram of proband. A, Sinus bradycardia and multiform premature ventricular contractions obtained as a rhythm strip during recording of a standard electrocardiogram. B, Polymorphic ventricular tachycardia recorded during ambulatory electrocardiogram (Holter monitor).
Figure 2
Figure 2
Genotype-phenotype features. A, Pedigree. Square symbols depict male subjects, and circles depict female subjects. Cross-hatching indicates unknown status. The occurrence of ventricular arrhythmia, periodic paralysis and dysmorphic features are depicted by small darkened quadrants. A box around the identifying number denotes the presence of R67W. B, Electrocardiographic recordings from four female subjects with ventricular arrhythmia. C, C→T transition (C199T), which alters the coding sense from arginine to tryptophan (R67W), shown in the forward (F) direction. D, Dysmorphic features, including (clockwise, from bottom left) small mandible, hypertelorism, syndactyly of toes (black arrow), bicuspid aortic valve (the white arrows point to line of leaflet coaptation, indicating a bicuspid valve), and clinodactyly, observed in five different family members.
Figure 3
Figure 3
KCNJ2-induced currents in human tsA201 cells and Xenopus oocytes. Shown are representative Ba+2-sensitive potassium currents obtained from tsA201 cells expressing WT (A) and R67W (B) KCNJ2. The solid line next to the current traces indicates the zero current level. Currents were measured from a holding potential of −90 mV to potentials from −140 to +40 mV, in 20-mV steps. C, Current-voltage relationships for tsA201 cells expressing WT (squares) or R67W KCNJ2 (circles). Whole-cell currents were measured at 400 ms after the start of the voltage pulse. The expression of WT KCNJ2 generated current, whereas expression of the R67W mutant did not elicit detectable current. Data represent mean ± SEM (n⩾4 cells). D, Ba+2-sensitive K+ currents measured at −150 mV, 50 ms after the start of the voltage pulse in Xenopus oocytes injected with WT KCNJ2 (4 ng), R67W KCNJ2 (4 ng) or coinjected with WT (2 ng) and R67W (2 ng) RNAs. Injection of WT RNA generated current, whereas no currents were detected after injection of R67W RNA or coinjection of both WT and mutant RNAs. Current measured in water-injected oocytes is shown for comparison. Data represent mean ± SEM (n=5–12 oocytes).
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References

Electronic-Database Information

    1. GenBank, http://www.ncbi.nlm.nih.gov/Genbank/ (for primers designed on the basis of accession number XM_008406)
    1. Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/Omim/ (for Andersen syndrome [MIM 170390])

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