Mutations in Kir2.1 Cause the Developmental and Episodic Electrical Phenotypes of Andersen's Syndrome

Abstract

Andersen's syndrome is characterized by periodic paralysis, cardiac arrhythmias, and dysmorphic features. We have mapped an Andersen's locus to chromosome 17q23 near the inward rectifying potassium channel gene KCNJ2. A missense mutation in KCNJ2 (encoding D71V) was identified in the linked family. Eight additional mutations were identified in unrelated patients. Expression of two of these mutations in Xenopus oocytes revealed loss of function and a dominant negative effect in Kir2.1 current as assayed by voltage-clamp. We conclude that mutations in Kir2.1 cause Andersen's syndrome. These findings suggest that Kir2.1 plays an important role in developmental signaling in addition to its previously recognized function in controlling cell excitability in skeletal muscle and heart.

17q24.2 microdeletions: a new syndromal entity with intellectual disability, truncal obesity, mood swings and hallucinations

“…As mentioned earlier, the deletion of patient 4 includes KCNJ2 of which heterozygous mutations are causal for Andersen syndrome. 37 This syndrome is characterized by periodic paralysis, ventricular arrhythmias and prolonged QT intervals, dental anomalies, small hands and feet, low-set ears, hypertelorism, micrognathia, fifth-digit clinodactyly and syndactyly. Also, joint laxity has been reported.…”

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

“…[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.…”

Pharmacological approach to the treatment of long and short QT syndromes

“…It has also been reported that pausedependence of TdP is predominant in LQT2 patient and rare in LQT1 and LQT3 (Tan et al, 2006). Similarly, exercise or mental stress has been reported to be a trigger for ventricular arrhythmias in LQT4 patients (Mohler et al, 2003) and hypokalemia is often associated with frequent ventricular arrhythmia in LQT7 (Plaster et al, 2001). Information on genotypespecific triggers can enable physicians to take patient-tailored approach in recommending physical and sports related activities and avoiding specific triggers in LQTS patients.…”

“…The newer more detailed classification scheme is based on the genetic mutation involved. Ten forms of congenital LQTS have been identified due to mutations in genes encoding for potassium channels, sodium channels or membrane components located on chromosome 3, 4, 6, 7, 11, 17 and 21 (Table 1) (Andersen et al, 1971;Tawil et al, 1994;Splawski et al, 2000;Plaster et al, 2001;Mohler et al, 2003;Splawski et al, 2004;Vatta et al, 2006;Medeiros-Domingo et al, 2007).…”

“…Also, Priori et al (2003) has reported that QTc is generally longer in LQT2 and LQT3 as compared to LQT1. Biphasic T waves following long pauses are commonly observed in the LQT4 (Plaster et al, 2001). Patient with LQT7 generally shows normal or near normal QT interval and the U waves are usually prominent and separated from the T wave (Mohler et al, 2003).…”