TY - JOUR
T1 - Mutations in JPH2-encoded junctophilin-2 associated with hypertrophic cardiomyopathy in humans
AU - Landstrom, Andrew P.
AU - Weisleder, Noah
AU - Batalden, Karin B.
AU - Martijn Bos, J.
AU - Tester, David J.
AU - Ommen, Steve R.
AU - Wehrens, Xander H.T.
AU - Claycomb, William C.
AU - Ko, Jae Kyun
AU - Hwang, Moonsun
AU - Pan, Zui
AU - Ma, Jianjie
AU - Ackerman, Michael J.
N1 - Funding Information:
MJA's research program is supported by the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program, the Dr. Scholl Foundation, the CJ Foundation for SIDS, the Doris Duke Charitable Foundation (clinical scientist development award), the American Heart Association (established investigator award) and the National Institutes of Health (NIH-HD42569). JM is supported by the NIH (AG15556, HL69000, CA95739). NW is supported by an American Heart Association Postdoctoral Fellowship.
PY - 2007/6
Y1 - 2007/6
N2 - Junctophilin-2 (JPH2) is a cardiac specific member of the junctophilins, a newly characterized family of junctional membrane complex proteins important in physically approximating the plasmalemmal L-type calcium channel and the sarcoplasmic reticulum ryanodine receptor for calcium-induced calcium release. JPH2 knockout mice showed disrupted calcium transients, altered junctional membrane complex formation, cardiomyopathy, and embryonic lethality. Furthermore, JPH2 gene expression is down-regulated in murine cardiomyopathy models. To this end, we explored JPH2 as a novel candidate gene for the pathogenesis of hypertrophic cardiomyopathy (HCM) in humans. Using polymerase chain reaction, denaturing high performance liquid chromatography, and direct DNA sequencing, comprehensive open reading frame/splice site mutational analysis of JPH2 was performed on DNA obtained from 388 unrelated patients with HCM. HCM-associated JPH2 mutations were engineered and functionally characterized using immunocytochemistry, cell morphometry measurements, and live cell confocal calcium imaging. Three novel HCM-susceptibility mutations: S101R, Y141H and S165F, which localize to key functional domains, were discovered in 3/388 unrelated patients with HCM and were absent in 1000 ethnic-matched reference alleles. Functionally, each human mutation caused (i) protein reorganization of junctophilin-2, (ii) perturbations in intracellular calcium signaling, and (iii) marked cardiomyocyte hyperplasia. The molecular and functional evidence implicates defective junctophilin-2 and disrupted calcium signaling as a novel pathogenic mechanism for HCM and establishes HCM as the first human disease associated with genetic defects in JPH2. Whether susceptibility for other cardiomyopathies, such as dilated cardiomyopathy, can be conferred by mutations in JPH2 warrants investigation.
AB - Junctophilin-2 (JPH2) is a cardiac specific member of the junctophilins, a newly characterized family of junctional membrane complex proteins important in physically approximating the plasmalemmal L-type calcium channel and the sarcoplasmic reticulum ryanodine receptor for calcium-induced calcium release. JPH2 knockout mice showed disrupted calcium transients, altered junctional membrane complex formation, cardiomyopathy, and embryonic lethality. Furthermore, JPH2 gene expression is down-regulated in murine cardiomyopathy models. To this end, we explored JPH2 as a novel candidate gene for the pathogenesis of hypertrophic cardiomyopathy (HCM) in humans. Using polymerase chain reaction, denaturing high performance liquid chromatography, and direct DNA sequencing, comprehensive open reading frame/splice site mutational analysis of JPH2 was performed on DNA obtained from 388 unrelated patients with HCM. HCM-associated JPH2 mutations were engineered and functionally characterized using immunocytochemistry, cell morphometry measurements, and live cell confocal calcium imaging. Three novel HCM-susceptibility mutations: S101R, Y141H and S165F, which localize to key functional domains, were discovered in 3/388 unrelated patients with HCM and were absent in 1000 ethnic-matched reference alleles. Functionally, each human mutation caused (i) protein reorganization of junctophilin-2, (ii) perturbations in intracellular calcium signaling, and (iii) marked cardiomyocyte hyperplasia. The molecular and functional evidence implicates defective junctophilin-2 and disrupted calcium signaling as a novel pathogenic mechanism for HCM and establishes HCM as the first human disease associated with genetic defects in JPH2. Whether susceptibility for other cardiomyopathies, such as dilated cardiomyopathy, can be conferred by mutations in JPH2 warrants investigation.
KW - Calcium
KW - Cardiomyopathy
KW - Genetics
KW - Hypertrophy
KW - JPH2
KW - Junctophilin
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U2 - 10.1016/j.yjmcc.2007.04.006
DO - 10.1016/j.yjmcc.2007.04.006
M3 - Article
C2 - 17509612
AN - SCOPUS:34249724562
SN - 0022-2828
VL - 42
SP - 1026
EP - 1035
JO - Journal of Molecular and Cellular Cardiology
JF - Journal of Molecular and Cellular Cardiology
IS - 6
ER -