title: Phenotype variability in patients carrying KCNJ2 mutations.
abstract: BACKGROUND
  Mutations of KCNJ2, the gene encoding the human inward rectifier potassium channel Kir2.1, cause Andersen-Tawil syndrome (ATS), a disease exhibiting ventricular arrhythmia, periodic paralysis, and dysmorphic features. However, some KCNJ2 mutation carriers lack the ATS triad and sometimes share the phenotype of catecholaminergic polymorphic ventricular tachycardia (CPVT). We investigated clinical and biophysical characteristics of KCNJ2 mutation carriers with "atypical ATS."
  
  
  RESULTS
  Mutational analyses of KCNJ2 were performed in 57 unrelated probands showing typical (≥2 ATS features) and atypical (only 1 of the ATS features or CPVT) ATS. We identified 24 mutation carriers. Mutation-positive rates were 75% (15/20) in typical ATS, 71% (5/7) in cardiac phenotype alone, 100% (2/2) in periodic paralysis, and 7% (2/28) in CPVT. We divided all carriers (n=45, including family members) into 2 groups: typical ATS (A) (n=21, 47%) and atypical phenotype (B) (n=24, 53%). Patients in (A) had a longer QUc interval [(A): 695 ± 52 versus (B): 643 ± 35 ms] and higher U-wave amplitude (0.24 ± 0.07 versus 0.18 ± 0.08 mV). C-terminal mutations were more frequent in (A) (85% versus 38%, P<0.05). There were no significant differences in incidences of ventricular tachyarrhythmias. Functional analyses of 4 mutations found in (B) revealed that R82Q, R82W, and G144D exerted strong dominant negative suppression (current reduction by 95%, 97%, and 96%, respectively, versus WT at -50 mV) and T305S moderate suppression (reduction by 89%).
  
  
  CONCLUSIONS
  KCNJ2 gene screening in atypical ATS phenotypes is of clinical importance because more than half of mutation carriers express atypical phenotypes, despite their arrhythmia severity.
authors.affiliation: Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Japan. horie@belle.shiga-med.ac.jp
authors.forename: Hiromi
authors.initials: H
authors.lastname: Kimura
authors.forename: Jun
authors.initials: J
authors.lastname: Zhou
authors.forename: Mihoko
authors.initials: M
authors.lastname: Kawamura
authors.forename: Hideki
authors.initials: H
authors.lastname: Itoh
authors.forename: Yuka
authors.initials: Y
authors.lastname: Mizusawa
authors.forename: Wei-Guang
authors.initials: WG
authors.lastname: Ding
authors.forename: Jie
authors.initials: J
authors.lastname: Wu
authors.forename: Seiko
authors.initials: S
authors.lastname: Ohno
authors.forename: Takeru
authors.initials: T
authors.lastname: Makiyama
authors.forename: Akashi
authors.initials: A
authors.lastname: Miyamoto
authors.forename: Nobu
authors.initials: N
authors.lastname: Naiki
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.forename: Yu
authors.initials: Y
authors.lastname: Xie
authors.forename: Tsugutoshi
authors.initials: T
authors.lastname: Suzuki
authors.forename: Shigeru
authors.initials: S
authors.lastname: Tateno
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Wei-Jin
authors.initials: WJ
authors.lastname: Zang
authors.forename: Makoto
authors.initials: M
authors.lastname: Ito
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Matsuura
authors.forename: Minoru
authors.initials: M
authors.lastname: Horie
mesh_terms: D000293:Adolescent; D000328:Adult; D050030:Andersen Syndrome / Q000453:epidemiology / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D009154:Mutation; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D024661:Potassium Channels, Inwardly Rectifying / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D015995:Prevalence; D017180:Tachycardia, Ventricular / Q000453:epidemiology / Q000235:genetics; D055815:Young Adult; D000098850:Polymorphic Catecholaminergic Ventricular Tachycardia
chemical_list: C489461:Kir2.1 channel; D024661:Potassium Channels, Inwardly Rectifying