Submission Details

JPH2 was first reported in relation to dilated cardiomyopathy (DCM) in 2016 (Sabater-Molina et al., 2016, PMID 27471098). Previously, JPH2 was curated for a semi-dominant mode of inheritance in DCM as evidence existed for both a dominant and recessive disease mechanism (curated 10/09/2020). The gene has now been curated separately for dominant disease here. The JPH2 gene encodes Junctophilin 2, a component of the junctional membrane complex (T-tubular and sarcoplasmic reticulum (SR) membranes) that is involved in excitation-contraction coupling (also known as Ca2+ induced Ca2+ release. In humans 4 junctophilin (JPH) genes are present. JPH2 is the predominant isoform in the heart (Takeshima et al., 2000, PMID 10949023). Human genetic evidence supporting this gene-disease relationship includes limited case-level data and segregation data. At least 7 rare missense variants, and a single promoter/exonic deletion of JPH2 have been observed in humans affected with (Hazebroek et al 2018, PMID: 29540472; van Lint et al 2019, PMID: 30847666; Lian et al 2023, PMID: 37461109; Lesurf et al 2022, PMID: 35288587) Limited co-segregation with disease was observed in a single family with DCM and a JPH2 missense variant (Sabater-Molina et al., 2016, PMID 27471098). Of note, beyond a single case (Lesurf et al) there are no reports of heterozygotes for variants predicted to cause haploinsufficiency being affected with DCM. In addition, this gene-disease assertion is supported by animal models. A DCM mouse model (MLPKO mice) showed an approximately 40% decreased JPH2 protein (but not mRNA) expression in left ventricular tissue (Minamisawa et al., 2004, PMID 15541368). Several JPH2 knock-out/down mice models have been made. A conventional knockout (KO) of the endogenous gene induced embryonic lethality and KO-cardiomyocytes show no rhythmic contraction and infirm Ca2+ transients (Takeshima et al., 2000, PMID 10949023). In an inducible JPH2 knockdown mouse model (using tamoxifen inducible cardiac-specific short-hairpin-RNA-mediated JPH2 knockdown), adult male tamoxifen-treated mice showed increased mortality and dilated cardiomyopathy. A cross of these mice with a JPH2-overexpression mouse also demonstrated phenotype recue due to JPH2 over-expression (van Oort et al., 2011, PMID 21339484). Another JPH2 knockdown mouse model (using cardiac-specific short-hairpin-RNA-mediated JPH2 knockdown; alphaMHCshJPH2) developed heart failure marked by reduced ejection fraction, ventricular dilation, and premature death (Reynolds et al., 2013, PMID 23715556). Finally, two Drosophila models in which JPH is overexpressed (UAS–jp) or knocked down (UAS-jpRNAi) using the Gal4/UAS system resulted in reduced survival and a DCM like phenotype (increased end-systolic (ESD), end-diastolic diameter (EDD) and decreased fractional shortening (FS)) without evidence for cardiac hypertrophy (Calpena et al., 2018, PMID 29208631). In summary, there is limited evidence to support a dominant model of disease for this gene-disease relationship. Further evidence over time is needed to establish the relationship of JPH2 with dominant DCM. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on January 24, 2025 (SOP Version 10).