title: KCNJ2 mutation results in Andersen syndrome with sex-specific cardiac and skeletal muscle phenotypes.
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.
authors.affiliation: Department of Pediatrics, Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, 45229, USA.
authors.forename: Gregor
authors.initials: G
authors.lastname: Andelfinger
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Tapper
authors.forename: Richard C
authors.initials: RC
authors.lastname: Welch
authors.forename: Carlos G
authors.initials: CG
authors.lastname: Vanoye
authors.forename: Alfred L
authors.initials: AL
authors.lastname: George
authors.forename: D Woodrow
authors.initials: DW
authors.lastname: Benson
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000503:physiopathology*; D001483:Base Sequence; D004553:Electric Conductivity; D004562:Electrocardiography; D005260:Female; D005838:Genotype; D006330:Heart Defects, Congenital / Q000235:genetics* / Q000503:physiopathology*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000503:physiopathology*; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics*; D012727:Sex Characteristics; D013577:Syndrome
chemical_list: D024661:Potassium Channels, Inwardly Rectifying