%0 Journal Article
%T Expression of a Mutant kcnj2 Gene Transcript in Zebrafish
%A Ivone U. S. Leong
%A Jonathan R. Skinner
%A Andrew N. Shelling
%A Donald R. Love
%J ISRN Molecular Biology
%D 2014
%R 10.1155/2014/324839
%X Long QT 7 syndrome (LQT7, also known as Andersen-Tawil syndrome) is a rare autosomal-dominant disorder that causes cardiac arrhythmias, periodic paralysis, and dysmorphic features. Mutations in the human KCNJ2 gene, which encodes for the subunit of the potassium inwardly-rectifying channel ( ), have been associated with the disorder. The majority of mutations are considered to be dominant-negative as mutant proteins interact to limit the function of wild type KCNJ2 proteins. Several LQT7 syndrome mouse models have been created that vary in the physiological similarity to the human disease. To complement the LQT7 mouse models, we investigated the usefulness of the zebrafish as an alternative model via a transient approach. Initial bioinformatic analysis identified the zebrafish orthologue of the human KCNJ2 gene, together with a spatial expression profile that was similar to that of human. The expression of a kcnj2-12 transcript carrying an in-frame deletion of critical amino acids identified in human studies resulted in embryos that exhibited defects in muscle development, thereby affecting movement, a decrease in jaw size, pupil-pupil distance, and signs of scoliosis. These defects correspond to some phenotypes expressed by human LQT7 patients. 1. Introduction Long QT 7 syndrome (LQT7, also known as Andersen-Tawil syndrome) is a rare autosomal-dominant disorder that causes periodic paralysis, ventricular arrhythmias with QT-prolongation, and dysmorphic features, which may not be present in all affected individuals. The dysmorphic features include scoliosis (curvature of the spine), clinodactyly (permanent lateral or medial curve of a finger or toe), wide-set eyes, low set or slanted ears, small jaw, and broad forehead [1]. Mutations in the human KCNJ2 gene, which encodes the potassium inwardly rectifying channel ( ) subunit, have been associated with the disorder. The KCNJ2 gene is expressed in the heart, brain, lung, skeletal muscle, kidney, and the eyes [2¨C4]. In the heart, the channel is involved in the resting phase of the cardiac action potential (AP) cycle. The KCNJ2 protein consists of two transmembrane domains encompassing a selective pore region. There are currently 38 mutations reported in the Inherited Arrhythmias Database (http://www.fsm.it/cardmoc/), and 19 of these mutations have dominant-negative effects. Many of these mutations have been characterised by electrophysiological measurements of transfected CHO cells. This in vitro system is widely used, but for the purposes of functional studies, in vivo modelling is the approach-of-choice.
%U http://www.hindawi.com/journals/isrn.molecular.biology/2014/324839/