Authors
Quinn CJ, Lahiri SK, Quick AP, Brandenburg S, Uhlenkamp D, Jain A, Moreira LM, Jung SY, Reilly S, Sayeed R, Krasopoulos G, Lehnart SE, Wehrens XHT
Journal
IJC Heart & Vasculature
Citation
IJC Heart & Vasculature 66 (2026) 102005.
Abstract
Background
Most mutations causing hypertrophic cardiomyopathy (HCM) affect sarcomeric proteins. Mutations in junctophilin-2 (JPH2) are also implicated, but the underlying mechanisms remain unclear. An A405S variant in JPH2 was identified in a male adolescent patient with interventricular septal (IVS) hypertrophy. The corresponding mouse variant (A399S) produces comparable IVS hypertrophy, establishing causality. Prior data indicated that altered intracellular Ca2+ handling is unlikely to be the primary driver.
Methods
We generated a CRISPR knock-in mouse model carrying the JPH2-A399S variant. Co-immunoprecipitation mass spectrometry and STED nanoscopy were used to identify JPH2 binding partners. Reactive oxygen species (ROS) were assessed with dihydroethidium in isolated myocytes. Adeno-associated virus serotype 9 (AAV9) was employed to overexpress peroxiredoxin 6 (PRDX6) in mutant hearts.
Results
PRDX6 was identified as a novel and abundant JPH2-interacting protein. PRDX6 expression was selectively downregulated in the IVS of JPH2-A399S mice and was also reduced in human failing hearts. JPH2-A399S mice exhibited increased ROS levels specifically in IVS myocytes. AAV9-mediated PRDX6 overexpression reversed the IVS hypertrophy phenotype.
Conclusions
These findings identify PRDX6 downregulation and consequent oxidative stress as a key mechanism driving JPH2-A399S-associated HCM. The results reveal a previously unrecognized role for JPH2 in cardiometabolic regulation and suggest that restoring PRDX6 levels may represent a therapeutic strategy for this form of HCM.
