P.12.10 Exome sequencing analysis reveals a mutation of Kir3.4 in a patient with Andersen–Tawil syndrome

Abstract

Periodic paralysis is a group of heterogeneous disorders caused by mutations of several ion channel genes including sodium, calcium and potassium channels. Andersen–Tawil syndrome (ATS) is a form of periodic paralysis, characterized by a triad of periodic muscle weakness, cardiac arrhythmia and dysmorphic features. KCNJ2 gene, which encodes Kir2.1 subunit and forms inward rectifying potassium channel (IRK), is known to be responsible for ATS but only about 60% of the ATS patients harbor KCNJ2 mutations suggesting other causative genes. We employed an exome capture resequencing analysis to identify a genetic cause of ATS patient with no mutations in KCNJ2 . The proband was from a family with dominantly inherited arrhythmia, and exhibited episodic muscle weakness with reduced serum potassium concentration and prominent U waves on ECG. Exome capture resequencing analysis, which was restricted to 162 ion channels and related genes, revealed a mutation of KCNJ5 encoding Kir3.4 subunit. In heart, Kir3.4 assembles with Kir3.1 to form G-protein-activated inward rectifying potassium (GIRK) channel, which is predominantly expressed in atria and contributes regulation of heart rate by acetylcholine, but the function of GIRK channels in skeletal muscle has not been well-elucidated. Immunoblot revealed significant expression of Kir3.4 protein in human skeletal muscle. We suspected the possibility of heteromerical assembly of Kir3.4 with Kir2.1 in skeletal muscle. The functional consequences of the mutation were investigated using the channels heterologously expressed in Xenopus oocytes. When Kir2.1 was expressed with mutant Kir3.4, the inward rectifying current was significantly smaller compared to that with WT Kir3.4. There is no direct evidence for the heteromerization of Kir3.4 with Kir2.1 subunit in native tissue but the dominant negative effect of mutant Kir3.4 on IRK may well explain the clinical presentation of both skeletal and heart muscles.