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Junctophilin-2 (JPH2) is a cardiac-specific membrane protein that bridges the transverse tubule and sarcoplasmic reticulum, ensuring precise excitation–contraction coupling. Variants in JPH2 have been implicated in autosomal dominant hypertrophic cardiomyopathy (HCM), characterized by unexplained left ventricular hypertrophy and increased risk of arrhythmia. Genetic and experimental evidence supports a pathogenic role for missense mutations in JPH2 leading to HCM.
Autosomal dominant JPH2 missense variants have been reported in at least 24 unrelated HCM probands, with co-segregation observed in six families (PMID:34861382). Key variants include c.482C>A (p.Thr161Lys) identified in nine Finnish pedigrees with 20 affected individuals and a penetrance of 71% by age 60 (PMID:30235249), as well as c.301A>C (p.Ser101Arg) and c.494C>T (p.Ser165Phe) found in 3/388 unrelated HCM patients with functional domain localization (PMID:17509612). Additional heterozygous variants c.421T>C (p.Tyr141His) and c.1306C>T (p.Arg436Cys) were statistically enriched in Japanese HCM cohorts versus controls (PMID:17476457).
Functional studies demonstrate that JPH2 missense mutations perturb intracellular calcium signaling and cardiomyocyte structure. Patient-derived iPSC-CMs carrying p.Thr161Lys exhibit cellular hypertrophy, sarcomeric disarray, prolonged action potentials and increased arrhythmogenicity compared to isogenic controls (PMID:37371654). Transgenic mice expressing the A405S variant (residue A399S in mice) develop basal septal hypertrophy and diastolic dysfunction mirroring human HCM (PMID:28393127). These data establish a dominant-negative mechanism through impaired JPH2 localization and calcium channel coupling.
JPH2 loss-of-function models further underscore its essential role in cardiac physiology: JPH2 knockout mice die of embryonic cardiac arrest with disrupted junctional membrane complexes, whereas shRNA-mediated knockdown in adult mouse hearts induces transverse-tubule loss, calcium mishandling and heart failure. Rescue of junctional membrane complex integrity upon re-expression of wild-type JPH2 confirms haploinsufficiency is insufficient to maintain cardiac function.
No substantial conflicting reports have been identified for JPH2 in HCM. While population databases record rare JPH2 variants, their frequency is far below disease prevalence and none are reported at high allele frequencies in healthy cohorts.
In summary, autosomal dominant missense variants in JPH2 produce a consistent HCM phenotype through disrupted calcium handling and myocyte architecture. Genetic testing for JPH2 variants is warranted in HCM patients negative for sarcomeric gene mutations. Future studies may explore targeted therapies aimed at stabilizing JPH2–ryanodine receptor interactions.
Key Take-home: JPH2 missense mutations cause autosomal dominant HCM by impairing junctophilin-2–mediated calcium coupling, supporting its clinical utility in genetic diagnostics.
Gene–Disease AssociationStrong≥24 unrelated HCM probands, co-segregation in 6 families, concordant functional data Genetic EvidenceStrong24 probands with autosomal dominant missense variants, co-segregation in six pedigrees Functional EvidenceModerateMultiple patient-derived iPSC and animal models demonstrating disrupted Ca2+ handling and hypertrophic phenotype |