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Genotype‐phenotype correlations of KCNJ2 mutations in Japanese patients with Andersen‐Tawil syndrome
Author(s) -
Haruna Yoshisumi,
Kobori Atsushi,
Makiyama Takeru,
Yoshida Hidetada,
Akao Masaharu,
Doi Takahiro,
Tsuji Keiko,
Ono Seiko,
Nishio Yukiko,
Shimizu Wataru,
Inoue Takehiko,
Murakami Tomoaki,
Tsuboi Naoya,
Yamanouchi Hideo,
Ushinohama Hiroya,
Nakamura Yoshihide,
Yoshinaga Masao,
Horigome Hitoshi,
Aizawa Yoshifusa,
Kita Toru,
Horie Minoru
Publication year - 2007
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.9483
Subject(s) - periodic paralysis , penetrance , phenotype , medicine , biology , long qt syndrome , mutation , qt interval , genotype , ventricular tachycardia , cardiology , genetics , endocrinology , gene , paralysis , surgery
Andersen‐Tawil syndrome (ATS) is a rare inherited disorder characterized by periodic paralysis, mild dysmorphic features, and QT or QU prolongation with ventricular arrhythmias in electrocardiograms (ECGs). Mutations of KCNJ2 , encoding the human inward rectifying potassium channel Kir 2.1, have been identified in patients with ATS. We aimed to clarify the genotype‐phenotype correlations in ATS patients. We screened 23 clinically diagnosed ATS patients from 13 unrelated Japanese families. Ten different forms of KCNJ2 mutations were identified in the 23 ATS patients included in this study. Their ECGs showed normal QTc intervals and abnormal U waves with QUc prolongation and a variety of ventricular arrhythmias. Especially, bidirectional ventricular tachycardia (VT) was observed in 13 of 23 patients (57%). Periodic paralysis was seen in 13 of 23 carriers (57%), dysmorphic features in 17 (74%), and seizures during infancy in 4 (17%). Functional assays for the two novel KCNJ2 mutations (c. 200G>A (p. R67Q) and c. 436G>A (p. G146S)) displayed no functional inward rectifying currents in a heterologous expression system and showed strong dominant negative effects when co‐expressed with wild‐type KCNJ2 channels (91% and 84% reduction at –50 mV respectively compared to wild‐type alone). Immunocytochemistry and confocal imaging revealed normal trafficking for mutant channels. In our study, all of the clinically diagnosed ATS patients had KCNJ2 mutations and showed a high penetrance with regard to the typical cardiac phenotypes: predominant U wave and ventricular arrhythmias, typically bidirectional VT. © 2007 Wiley‐Liss, Inc.