Mutation of junctophilin type 2 associated with hypertrophic cardiomyopathy.
Junctophilin subtypes, designated as JPH1 approximately 4, are protein components of junctional complexes and play essential roles in cellular Ca2+ signaling in excitable cells. Knockout mice lacking the cardiac-type Jph2 die of embryonic cardiac arrest, and the mutant cardiac myocytes exhibit impaired formation of peripheral couplings and arrhythmic Ca2+ signaling caused by functional uncoupling between dihydropyridine and ryanodine receptor channels. Based on these observations, we hypothesized that mutations of JPH2 could cause human genetic cardiac diseases. Among 195 Japanese patients (148 index cases and 47 affected family members) with hypertrophic cardiomyopathy (HCM), two heterozygous nonsynonymous nucleotide transitions, G505S and R436C, were newly found in JPH2. When Fisher's exact test was used to compare index cases with HCM to unrelated Japanese healthy controls in the frequencies of mutant alleles, only the G505S mutation showed statistical significance (4/296 HCM patients and 0/472 control individuals, P=0.022). This result was still significant after Bonferroni's correction for multiple comparisons (P=0.044). To the best of our knowledge, this is the first report on JPH2 mutation associated with HCM.
Matsushita
Yoshihisa
Y
International Research and Educational Institute for Integrated Medical Sciences, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan.|Division of Integrated Medical Sciences, Institute of Advanced Biomedical Engineering and Science, Graduate School of Medicine, Tokyo Women's Medical University, Tokyo, Japan.
Furukawa
Toru
T
International Research and Educational Institute for Integrated Medical Sciences, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan.|Division of Integrated Medical Sciences, Institute of Advanced Biomedical Engineering and Science, Graduate School of Medicine, Tokyo Women's Medical University, Tokyo, Japan.
Kasanuki
Hiroshi
H
Department of Cardiology, Tokyo Women's Medical University, Tokyo, Japan.
Nishibatake
Makoto
M
Department of Pediatrics, Kagoshima Seikyo General Hospital, Kagoshima, Japan.
Kurihara
Yachiyo
Y
Department of Pediatrics, St. Marianna University School of Medicine, Kawasaki, Japan.
Ikeda
Atsushi
A
Department of Biological Chemistry, Kyoto University Graduate School of Pharmaceutical Science, Kyoto, Japan.
Kamatani
Naoyuki
N
Division of Genomic Medicine, Department of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, Tokyo, Japan.
Takeshima
Hiroshi
H
Department of Biological Chemistry, Kyoto University Graduate School of Pharmaceutical Science, Kyoto, Japan.
Matsuoka
Rumiko
R
International Research and Educational Institute for Integrated Medical Sciences, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan. rumiko@imcir.twmu.ac.jp.|Division of Integrated Medical Sciences, Institute of Advanced Biomedical Engineering and Science, Graduate School of Medicine, Tokyo Women's Medical University, Tokyo, Japan. rumiko@imcir.twmu.ac.jp.|Division of Pediatric Cardiology, Tokyo Women's Medical University, Tokyo, Japan. rumiko@imcir.twmu.ac.jp.
D020013:Calcium Signaling; D002312:Cardiomyopathy, Hypertrophic / Q000209:etiology / Q000235:genetics*; D016022:Case-Control Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation
D008565:Membrane Proteins; C412507:junctophilin