Previously, missense variants in JPH2 have been linked to hypertrophic cardiomyopathy; however, pathogenic "loss of function" (LOF) variants have not been described.
We identified 20 individuals affected with HCM with or without systolic heart failure and conduction abnormalities in the nine Finnish families with JPH2p.(Thr161Lys) variant.
Human junctophilin-2 undergoes a structural rearrangement upon binding PtdIns(3,4,5)P3 and the S101R mutation identified in hypertrophic cardiomyopathy obviates this response.
Among these are mutations in TNNC1- encoded cardiac troponin C, PLN-encoded phospholamban, and JPH2-encoded junctophilin 2 which have each been associated with HCM in multiple studies.
JPH2 expression was reduced in flash-frozen human cardiac tissue procured from patients with HCM compared with ostensibly healthy traumatic death victims.
Recent studies have revealed that mutations in the JPH2 gene are associated with hypertrophic cardiomyopathy, highlighting the importance of this protein for normal cardiac physiology.
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.
Among 195 Japanese patients (148 index cases and 47 affected family members) with hypertrophic cardiomyopathy (HCM), two heterozygous nonsynonymous nucleotide transitions, G505S and R436C, were newly found in JPH2.