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.

Cellular basis for electrocardiographic and arrhythmic manifestations of Andersen-Tawil syndrome (LQT7)

“…Patients with Andersen-Tawil syndrome having the heterozygous mis-sense mutation R67W in KCNJ2 have been found to display nonspecific ECG abnormalities but no QT prolongation, despite a history of syncope and frequent ventricular premature beats. 6 Biophysical characterization of R67W demonstrated loss of function and a dominant-negative effect on Kir2.1 current. In contrast to the clinical experience, our results demonstrate that I K1 block consistently prolongs APD and QT interval.…”

“…[1][2][3][4][5][6] This skeletal muscle syndrome is associated with periodic paralysis often linked to fluctuations in plasma potassium levels. 2,7,8 Clinical studies indicate that Andersen-Tawil syndrome may be associated with arrhythmias, particularly when aggravated by other health problems such as infection.…”

Management and Treatment of Andersen-Tawil Syndrome (ATS)

“…There is still no consensus as to the possible sex-dependent effect of the KCNJ2 mutation and the likelihood of expressing BVT. Andelfinger et al 8 described a 71-member family with clinical and genetically defined ATS1 in which 13 (81%) of 16 mutation-positive females expressed BVT compared with none present in the 25 mutation-positive males. Other studies exploring phenotypic variability concluded that no sex-dependent phenotypic differences were present in ATS1.…”

SK3-1C, a Dominant-negative Suppressor of SKCa and IKCa Channels

“…tissues (7, 16, 22, 40 -49). However, experiments in heterologous expression systems have shown them to act as specific dominant-negative suppressors of their functional counterparts (7,16,22,42,(45)(46)(47)(48). Since SK3-1C did not produce functional channels when expressed heterologously in mammalian cells (data not shown), we used the approach described for other non-functional K ϩ channel isoforms to ascertain whether SK3-1C exhibits dominantinhibitory activity.…”

“…Similar truncation mutants of Kv1.1 underlie episodic ataxia type-1 (49,64), and truncation mutants of KCNQ2 and KCNQ3 are responsible for benign familial neonatal convulsion. Dominant-inhibitory nonfunctional mutants of K ir 2.1/KCNJ2 contribute to Andersen's syndrome, a developmental disorder with an accompanying ventricular tachycardia (48). Thus, dominant-negative suppression may be a widespread phenomenon through which the functional expression of multimeric proteins such as K ϩ channels is regulated, leading to gradations in the levels of membrane excitability.…”