Abstract
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 humanKCNJ2gene, which encodes for the subunit of the potassium inwardly-rectifying channel (IK1), 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 humanKCNJ2gene, together with a spatial expression profile that was similar to that of human. The expression of akcnj2-12transcript 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.
Highlights
Long QT 7 syndrome (LQT7, known as AndersenTawil syndrome) is a rare autosomal-dominant disorder that causes periodic paralysis, ventricular arrhythmias with QTprolongation, and dysmorphic features, which may not be present in all affected individuals
The work described in this study shows that zebrafish has an orthologue of the human KCNJ2 gene, and the spatial expression profile is similar to the human
The temporal expression profile shows that kcnj2-12 may have a role in muscle development in zebrafish
Summary
Long QT 7 syndrome (LQT7, known as AndersenTawil syndrome) is a rare autosomal-dominant disorder that causes periodic paralysis, ventricular arrhythmias with QTprolongation, and dysmorphic features, which may not be present in all affected individuals. Mutations in the human KCNJ2 gene, which encodes the potassium inwardly rectifying channel (IK1) subunit, have been associated with the disorder. The KCNJ2 gene is expressed in the heart, brain, lung, skeletal muscle, kidney, and the eyes [2,3,4]. 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. Several LQT7 mouse models have been created and they are either Kcnj knockout mutants [5, 6], or over-express wild-type (WT) Kcnj protein [7, 8], or the model express a dominantnegative Kcnj protein [8, 9]
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