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

Abstract

Junctophilin-2 (JPH2) is a part of the junctional membrane complex that facilitates calcium-handling in the cardiomyocyte. Previously, missense variants in JPH2 have been linked to hypertrophic cardiomyopathy; however, pathogenic “loss of function” (LOF) variants have not been described. Family-based genetic analysis of GME individuals with cardiomyopathic disease identified an Iranian patient with dilated cardiomyopathy (DCM) as a carrier of a novel, homozygous single nucleotide insertion in JPH2 resulting in a stop codon (JPH2-p.E641*). A second Iranian family with consanguineous parents hosting an identical heterozygous variant had 2 children die in childhood from cardiac failure. To characterize ethnicity-dependent genetic variability in JPH2 and to identify homozygous JPH2 variants associated with cardiac disease, we identified variants in JPH2 in a worldwide control cohort (gnomAD) and 2 similar cohorts from the Greater Middle East (GME Variome, Iranome). These were compared against ethnicity-matched clinical whole exome sequencing (WES) referral tests and a case cohort of individuals with hypertrophic cardiomyopathy (HCM) based on comprehensive review of the literature. Worldwide, 1.45% of healthy individuals hosted a rare JPH2 variant with a significantly higher proportion among GME individuals (4.45%); LOF variants were rare overall (0.04%) yet were most prevalent in GME (0.21%). The increased prevalence of LOF variants in GME individuals was corroborated among region-specific, clinical WES cohorts. In conclusion, we report ethnic-specific differences in JPH2 rare variants, with GME individuals being at higher risk of hosting homozygous LOF variants. This conclusion is supported by the identification of a novel JPH2 LOF variant confirmed by segregation analysis resulting in autosomal recessive pediatric DCM due to presumptive JPH2 truncation.

The role of junctophilin proteins in cellular function

“…Various types of deficits in members of the junctophilin gene family have been associated with several inherited disorders. Autosomal-dominant and recessive variants in JPH2 have been linked to hypertrophic and dilated cardiomyopathy, respectively ( 180 , 181 ). JPH1 has been revealed as a modifier gene of a hereditary motor and sensory neuropathy known as Charcot-Marie-Tooth disease ( 182 ).…”

“…These variants are all predicted to truncate the JPH2 protein and have a severe loss-of-function phenotype. Jones et al ( 181 ) recently reported one of these pLOF variant (Glu641Ter) in 2 Iranian families. One proband who was homozygous for this variant was diagnosed at 20 mo of age with DCM.…”

Targeting JP2: A New Treatment for Pulmonary Hypertension

“…In addition to the change in JP2 expression level related to disease, according to the gene analysis results in patients with heart diseases, it has been confirmed that there are gene mutations in JP2 in some heart diseases, such as S101R, Y141H, T161L, S165F, and E169K mutations in the MORN region; A399S, 403S, and A405S mutations in the α-helix structure; and R436C and G505S mutations in the divergent domain [74][75][76][77][78][79].…”

Palmitoylation: A Fatty Regulator of Myocardial Electrophysiology

“…Junctophilin-2 is required to maintain T-tubule structure, RyR2 function, and is a requisite component of the excitation-contraction coupling machinery (Van Oort et al, 2011;Chen et al, 2013;Guo et al, 2014;Zhang et al, 2014). Not surprisingly, mutations in junctophilin-2 are associated with cardiomyopathy, arrhythmia, and heart failure (Beavers et al, 2013;Takeshima et al, 2015;Vanninen et al, 2018;Jones et al, 2019). Junctophilin-2 is a large, nearly 700 amino acid, predominantly cytoplasmic protein containing N-terminal MORN domains that associate with the plasma membrane and a C-terminal transmembrane domain embedded in the SR (Takeshima et al, 2015; Figure 2).…”