title: Mutations in JPH2-encoded junctophilin-2 associated with hypertrophic cardiomyopathy in humans.
abstract: 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.
authors.affiliation: Mayo Medical School, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Landstrom
authors.forename: Noah
authors.initials: N
authors.lastname: Weisleder
authors.forename: Karin B
authors.initials: KB
authors.lastname: Batalden
authors.forename: J Martijn
authors.initials: JM
authors.lastname: Bos
authors.forename: David J
authors.initials: DJ
authors.lastname: Tester
authors.forename: Steve R
authors.initials: SR
authors.lastname: Ommen
authors.forename: Xander H T
authors.initials: XH
authors.lastname: Wehrens
authors.forename: William C
authors.initials: WC
authors.lastname: Claycomb
authors.forename: Jae-Kyun
authors.initials: JK
authors.lastname: Ko
authors.forename: Moonsun
authors.initials: M
authors.lastname: Hwang
authors.forename: Zui
authors.initials: Z
authors.lastname: Pan
authors.forename: Jianjie
authors.initials: J
authors.lastname: Ma
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ackerman
mesh_terms: D020013:Calcium Signaling; D002312:Cardiomyopathy, Hypertrophic / Q000209:etiology / Q000235:genetics*; D016022:Case-Control Studies; D006801:Humans; D007150:Immunohistochemistry; D008565:Membrane Proteins / Q000235:genetics*; D009124:Muscle Proteins / Q000235:genetics*; D009154:Mutation
chemical_list: C000589041:JPH2 protein, human; D008565:Membrane Proteins; D009124:Muscle Proteins; C412507:junctophilin