Abstract
Junctophilin subtypes, designated as JPH1∼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.
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Acknowledgments
We are grateful to Dr. Bernardo Nadal-Ginard for his valuable comments and Dr. Katsumi Matsuzaki for his kind support on CD measurements. We thank Dr. Kazuo Momma for providing clinical information of the patients. We also thank Drs. Tsutomu Nishizawa, Shin-ichiro Imamura, Shoichi Arai, Yoshiyuki Furutani, Ms. Michiko Furutani, and Mr. Hiroaki Nagao for their excellent technical assistance, and Ms. Barbara Levene for editing the manuscript. This work was supported by the Program for Promoting the Establishment of Strategic Research Centers, Special Coordination Funds for Promoting Science and Technology, Ministry of Education, Culture, Sports, Science and Technology (Japan), a grant-in-aid from the Ministry of Education, Culture, Sports, Science and Technology (Japan), the Naito Foundation, the Sumitomo Foundation, and the Uehara Memorial Foundation.
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Matsushita, Y., Furukawa, T., Kasanuki, H. et al. Mutation of junctophilin type 2 associated with hypertrophic cardiomyopathy. J Hum Genet 52, 543–548 (2007). https://doi.org/10.1007/s10038-007-0149-y
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DOI: https://doi.org/10.1007/s10038-007-0149-y
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