Submission Details

JPH2 was first reported in relation to dilated cardiomyopathy (DCM) in 2016 (Sabater-Molina et al., 2016, PMID 27471098). Current evidence has been observed in both an autosomal dominant as well as an autosomal recessive mechanism. Therefore, JPH2 was curated for a semi-dominant mode of inheritance in DCM. 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). Plasma membrane depolarization triggers the opening of the voltage-gated Ca2+ channel (DHPR also known as L-type Ca2+ channel), allowing influx of calcium ions. This triggers the release of a great amount of Ca2+ from the SR via the ryanodine receptor resulting in heart muscle contraction. In humans 4 junctophilin (JPH) genes are present. JPH2 is the predominant isoform in the heart (Takeshima et al., 2000, PMID 10949023). The JPH protein contains at the carboxy-terminal a hydrophobic transmembrane domain that spans the SR membrane and at the cytoplasmic site a domain (containing MORN motifs) that shows specific affinity for the plasma membrane. In this way two important Ca2+ channels (DHPR and RYR2) are brought close together (Garbino & Wehrens, 2010, PMID 20694023). Human genetic evidence supporting this gene-disease relationship includes case-level data and segregation data. At least 8 variants related to DCM (including missense, nonsense, etc.) have been reported in humans (Hazebroek et al., 2018, PMID 29540472; Jones et al., 2019, PMID 31227780; Landrum et al., 2018, PMID 29165669; Sabater-Molina et al., 2016, PMID 27471098; Vasilescu et al., 2018, PMID 30384889). Co-segregation was observed in a single family with DCM and a JPH2 missense variant (Sabater-Molina et al., 2016, PMID 27471098). Homozygous nonsense variants in JPH2 have also been observed in severe, pediatric-onset DCM (Vasilescu et al, 2018, PMID 30384889; Jones et al., 2019, PMID 31227780). 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). In addition several JPH2 knock-out/down mice models have been made. A conventional knockout (KO) of the endogenous gene induced embryonic lethality (none survive beyond day E11.5). KO-cardiomyocytes show no rhythmic contraction and infirm Ca2+ transients (Takeshima et al., 2000, PMID 10949023). Inducible JPH2 knockdown mice (using tamoxifen inducible cardiac-specific short-hairpin-RNA-mediated JPH2 knockdown) were also made. Adult male tamoxifen treated mice showed increased mortality and dilated cardiomyopathy (end-systolic and end-diastolic diameter were both significantly larger) but no hypertrophic cardiomyopathy (van Oort et al., 2011, PMID 21339484). Another JPH2 knockdown mouse model (using cardiac-specific short-hairpin-RNA-mediated JPH2 knockdown; alphaMHCshJPH2) was generated (C57BL/6 background). At postnatal day 10 alphaMHC- shJPH2 mice develop heart failure marked by reduced ejection fraction, ventricular dilation, and premature death (Reynold et al., 2013, PMID 23715556). JPH2 knockdown mice (alphaMHCshJPH2) in a mixed background (FVB/C57BL/6) showed a delayed onset of the T-tubule maturation impairments, as well as an extended lifespan and no dilated cardiomyopathy but cardiac hypertrophy and heart failure (Chen et al., 2013, PMID 23860812). Finally two Drosophila models in which JPH is overexpressed (UAS–jp) or knocked down (UAS-jpRNAi) using the Gal4/UAS system result 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 moderate evidence to support this gene-disease relationship. More evidence is needed to establish the relationship of JPH2 with semidominant DCM definitively. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on July 24, 2020 (SOP Version 7).