title: Genotype-phenotype correlations of KCNJ2 mutations in Japanese patients with Andersen-Tawil syndrome.
abstract: 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.
authors.affiliation: Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Yoshisumi
authors.initials: Y
authors.lastname: Haruna
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kobori
authors.forename: Takeru
authors.initials: T
authors.lastname: Makiyama
authors.forename: Hidetada
authors.initials: H
authors.lastname: Yoshida
authors.forename: Masaharu
authors.initials: M
authors.lastname: Akao
authors.forename: Takahiro
authors.initials: T
authors.lastname: Doi
authors.forename: Keiko
authors.initials: K
authors.lastname: Tsuji
authors.forename: Seiko
authors.initials: S
authors.lastname: Ono
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Nishio
authors.forename: Wataru
authors.initials: W
authors.lastname: Shimizu
authors.forename: Takehiko
authors.initials: T
authors.lastname: Inoue
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Murakami
authors.forename: Naoya
authors.initials: N
authors.lastname: Tsuboi
authors.forename: Hideo
authors.initials: H
authors.lastname: Yamanouchi
authors.forename: Hiroya
authors.initials: H
authors.lastname: Ushinohama
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Masao
authors.initials: M
authors.lastname: Yoshinaga
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Horigome
authors.forename: Yoshifusa
authors.initials: Y
authors.lastname: Aizawa
authors.forename: Toru
authors.initials: T
authors.lastname: Kita
authors.forename: Minoru
authors.initials: M
authors.lastname: Horie
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D050030:Andersen Syndrome / Q000175:diagnosis* / Q000000981:diagnostic imaging / Q000235:genetics; D000818:Animals; D019556:COS Cells; D002648:Child; D002675:Child, Preschool; D002522:Chlorocebus aethiops; D004252:DNA Mutational Analysis; D004452:Echocardiography; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010245:Paralyses, Familial Periodic / Q000000981:diagnostic imaging / Q000235:genetics; D018408:Patch-Clamp Techniques; D010641:Phenotype; D024661:Potassium Channels, Inwardly Rectifying / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D017434:Protein Structure, Tertiary; D017180:Tachycardia, Ventricular / Q000000981:diagnostic imaging / Q000235:genetics
chemical_list: C489457:KCNJ2 protein, human; D024661:Potassium Channels, Inwardly Rectifying