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J Med Genet 2006 Aug 01;438:653-9. doi: 10.1136/jmg.2006.040816.
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Functional and clinical characterization of a mutation in KCNJ2 associated with Andersen-Tawil syndrome.

Lu CW , Lin JH , Rajawat YS , Jerng H , Rami TG , Sanchez X , DeFreitas G , Carabello B , DeMayo F , Kearney DL , Miller G , Li H , Pfaffinger PJ , Bowles NE , Khoury DS , Towbin JA .

Andersen-Tawil syndrome (ATS) is a rare inherited disorder, characterised by periodic paralysis, cardiac dysarrhythmias, and dysmorphic features, and is caused by mutations in the gene KCNJ2, which encodes the inward rectifier potassium channel, Kir2.1. This study sought to analyse KCNJ2 in patients with familial ATS and to determine the functional characteristics of the mutated gene.We screened a family with inherited ATS for the mutation in KCNJ2, using direct DNA sequencing. A missense mutation (T75R) of Kir2.1, located in the highly conserved cytoplasmic N-terminal domain, was identified in three affected members of this family. Using the Xenopus oocyte expression system and whole cell voltage clamp analyses, we found that the T75R mutant was non-functional and possessed a strong dominant negative effect when co-expressed with the same amount of wild type Kir2.1. Transgenic (Tg) mice expressing the mutated form of Kir2.1 in the heart had prolonged QTc intervals compared with mice expressing the wild type protein. Ventricular tachyarrhythmias were observed in 5 of 14 T75R-Tg mice compared with 1 of 7 Wt-Tg and none of 6 non-transgenic littermates. In three of five T75R-Tg mice with ventricular tachycardia, their ECG disclosed bidirectional tachycardia as in our proband.The in vitro studies revealed that the T75R mutant of Kir2.1 had a strong dominant negative effect in the Xenopus oocyte expression system. It still preserved the ability to co-assemble and traffic to the cell membrane in mammalian cells. For in vivo studies, the T75R-Tg mice had bidirectional ventricular tachycardia after induction and longer QT intervals.

PubMed ID: 16571646
PMC ID: PMC2564587
Article link: J Med Genet
Grant support: [+]

Species referenced: Xenopus
Genes referenced: col4a5 kcnj2
GO keywords: ATP-sensitive potassium channel complex

Disease Ontology terms: Andersen-Tawil syndrome
References [+] :
Ai, Novel KCNJ2 mutation in familial periodic paralysis with ventricular dysrhythmia. 2002, Pubmed, Xenbase