JPH2 – Dilated Cardiomyopathy

Autosomal recessive loss-of-function variants in JPH2 have been implicated in early-onset dilated cardiomyopathy (DCM). Family-based whole exome sequencing in Greater Middle Eastern cohorts identified an Iranian neonate with DCM homozygous for a single-nucleotide insertion in JPH2 (c.1920dup (p.Glu641Ter)) and confirmed segregation in a second consanguineous family with two affected siblings (PMID:31227780). Across control and clinical cohorts, loss-of-function JPH2 variants were rare (0.04%) but enriched in the GME population (0.21%), supporting a founder effect in this region.

Junctophilin-2 is essential for junctional membrane complex formation and calcium-induced calcium release in cardiomyocytes. JPH2 knockout and knock-in models demonstrate disrupted calcium transients, impaired excitation-contraction coupling, and heart failure phenotypes consistent with human DCM (PMID:17509612). These findings establish haploinsufficiency via truncating mutations as the mechanism underlying JPH2-related recessive DCM.

Key Take-home: Autosomal recessive truncating variants in JPH2 cause severe pediatric DCM through loss of junctional membrane integrity and perturbed calcium handling.

References

• Scientific reports • 2019 • Analysis of enriched rare variants in JPH2-encoded junctophilin-2 among Greater Middle Eastern individuals reveals a novel homozygous variant associated with neonatal dilated cardiomyopathy. PMID:31227780
• Journal of molecular and cellular cardiology • 2007 • Mutations in JPH2-encoded junctophilin-2 associated with hypertrophic cardiomyopathy in humans. PMID:17509612

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