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Neurology. 2014 Mar 25;82(12):1058-64. doi: 10.1212/WNL.0000000000000239. Epub 2014 Feb 26.

A Kir3.4 mutation causes Andersen-Tawil syndrome by an inhibitory effect on Kir2.1.

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From the Department of Neurology (Y.K., M.F., M.N., T.K., H.M., M.P.T.), and Laboratory of Integrative Physiology, Department of Physiology (S.S., Y. Okamura), Osaka University Graduate School of Medicine, Suita, Osaka; Division of Neurogenetics (T.N., K.O.), Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Aichi; Department of Cardiovascular and Respiratory Medicine (H.K., H.I., M.H.), Shiga University of Medical Science, Otsu, Shiga; Division of Arrhythmia and Electrophysiology (T.A., W.S.), Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Osaka; Department of Pediatrics (M.Y.), National Hospital Organization Kagoshima Medical Center, Kagoshima; Department of Neurology (Y. Osaki, K.S.), Kurashiki Central Hospital, Kurashiki, Okayama; Department of Legal Medicine (T.S.), Osaka Medical College, Takatsuki, Osaka; Department of Cardiology (K.K.), Kurashiki Central Hospital, Kurashiki, Okayama; and Department of Cardiovascular Medicine (W.S.), Nippon Medical School, Bunkyo, Tokyo, Japan. Y.K. is currently affiliated with the Department of Neurology, Osaka General Medical Center, Sumiyoshi, Osaka, Japan; and T.K. is currently affiliated with the Department of Biochemistry and Molecular Biology, Division of Biological Sciences, The University of Chicago, IL.



To identify other causative genes for Andersen-Tawil syndrome, which is characterized by a triad of periodic paralysis, cardiac arrhythmia, and dysmorphic features. Andersen-Tawil syndrome is caused in a majority of cases by mutations in KCNJ2, which encodes the Kir2.1 subunit of the inwardly rectifying potassium channel.


The proband exhibited episodic flaccid weakness and a characteristic TU-wave pattern, both suggestive of Andersen-Tawil syndrome, but did not harbor KCNJ2 mutations. We performed exome capture resequencing by restricting the analysis to genes that encode ion channels/associated proteins. The expression of gene products in heart and skeletal muscle tissues was examined by immunoblotting. The functional consequences of the mutation were investigated using a heterologous expression system in Xenopus oocytes, focusing on the interaction with the Kir2.1 subunit.


We identified a mutation in the KCNJ5 gene, which encodes the G-protein-activated inwardly rectifying potassium channel 4 (Kir3.4). Immunoblotting demonstrated significant expression of the Kir3.4 protein in human heart and skeletal muscles. The coexpression of Kir2.1 and mutant Kir3.4 in Xenopus oocytes reduced the inwardly rectifying current significantly compared with that observed in the presence of wild-type Kir3.4.


We propose that KCNJ5 is a second gene causing Andersen-Tawil syndrome. The inhibitory effects of mutant Kir3.4 on inwardly rectifying potassium channels may account for the clinical presentation in both skeletal and heart muscles.

[Indexed for MEDLINE]

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