Mutation in <scp>JPH2</scp> cause dilated cardiomyopathy

Sabater-Molina, María; Navarro, Marina; Sáez, Esperanza García-Molina; Garrido, Iris P.; Pascual-Figal, Domingo A.; Carrillo, J. González; Gimeno-Blanes, Juan Ramón

doi:10.1111/cge.12825

Cited by 21 publications

(15 citation statements)

References 6 publications

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“…Additionally, mutation in JPH2 can lead to dilated cardiomyopathy. Both results were interpreted as evidence of the regulatory role of JPH2 in skeletal muscle biology [ 49 , 50 ]. In the lamb vs. adult comparison, we noticed a unique lncRNA named TCONS_00583478 might target lipoma HMGIC fusion partner (LHFP), therefore, this lncRNA might be involved in muscle lipid metabolism.…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide Analysis Reveals Extensive Changes in LncRNAs during Skeletal Muscle Development in Hu Sheep

Ren

Deng

Fan

et al. 2017

Genes

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As an important type of noncoding RNA molecules, long non-coding RNAs (lncRNAs) act as versatile players in various biological processes. However, little is known about lncRNA regulators during sheep muscle growth. To explore functional lncRNAs during sheep muscle growth, we systematically investigated lncRNAs using strand-specific Ribo-Zero RNA sequencing at three key developmental stages in Hu sheep. A total of 6924 lncRNAs were obtained, and the differentially expressed lncRNAs and genes were screened from (control vs. experiment) fetus vs. lamb, lamb vs. adult, and fetus vs. adult comparisons, respectively. The quantitative real-time polymerase chain reaction (qRT-PCR) analysis results correlated well with the sequencing data. Moreover, functional annotation analysis based on the Gene Ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) databases showed that the target genes of the differentially expressed lncRNAs were significantly enriched in organ morphogenesis, skeletal system development as well as response to stimulus and some other terms related to muscle. Furthermore, a co-expression network of the differentially expressed target genes and lncRNAs was constructed and well-known muscle growth regulators such as retrotransposon-like 1 and Junctophilin-2 were included. Finally, we investigated the expression profiles of seven lncRNAs and their target genes, and found that they played vital roles in muscle growth. This study extends the sheep muscle lncRNA database and provides novel candidate regulators for future genetic and molecular studies on sheep muscle growth, which is helpful for optimizing the production of mutton.

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Section: Discussionmentioning

confidence: 99%

Genome-Wide Analysis Reveals Extensive Changes in LncRNAs during Skeletal Muscle Development in Hu Sheep

Ren

Deng

Fan

et al. 2017

Genes

View full text Add to dashboard Cite

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“…Studies have shown a high level of correlation between this pathological remodeling and a decrease in JPH2 expression [9, 14]. Mutations in JPH2 have been linked to both hypertrophic cardiomyopathy, in which the left ventricle thickens [26], and more recently, to dilated cardiomyopathy, a disorder in which the left ventricle dilates [27]. Moreover, downregulation of JPH2 levels has been observed in patients with hypertrophic cardiomyopathy [8].…”

Section: Discussionmentioning

confidence: 99%

Junctophilin-2 gene therapy rescues heart failure by normalizing RyR2-mediated Ca2+ release

Reynolds

Quick

Wang

et al. 2016

International Journal of Cardiology

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Background Junctophilin-2 (JPH2) is the primary structural protein for coupling of transverse (T)-tubule associated cardiac L-type Ca channels and type-2 ryanodine receptors on the sarcoplasmic reticulum within junctional membrane complexes in cardiomyocytes. Effective signaling between these channels ensures adequate Ca-induced Ca release required for normal cardiac contractility. Disruption of JMC subcellular domains, a common feature of failing hearts, has been attributed to JPH2 downregulation. Here, we tested the hypothesis that adeno-associated virus type 9 (AAV9) mediated overexpression of JPH2 could halt the development of heart failure in a mouse model of transverse aortic constriction (TAC). Methods and Results Following TAC, a progressive decrease in ejection fraction was paralleled by a progressive decrease of cardiac JPH2 levels. AAV9-mediated expression of JPH2 rescued cardiac contractility in mice subjected to TAC. AAV9-JPH2 also preserved T-tubule structure. Moreover, the Ca2+ spark frequency was reduced and the Ca2+ transient amplitude was increased in AAV9-JPH2 mice following TAC, consistent with JPH2-mediated normalization of SR Ca2+ handling. Conclusions This study demonstrates that AAV9-mediated JPH2 gene therapy maintained cardiac function in mice with early stage heart failure. Moreover, restoration of JPH2 levels prevented loss of T-tubules and suppressed abnormal SR Ca2+ leak associated with contractile failure following TAC. These findings suggest that targeting JPH2 might be an attractive therapeutic approach for treating pathological cardiac remodeling during heart failure.

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“…Seventeen of them are missense variants. Before this study, no convincing evidence of segregation within large pedigrees except for the p.(Glu85Lys) [ 25 ] and no de novo JPH2 mutations have been reported in patients with HCM. In 2007, Landstrom et al .…”

Section: Discussionmentioning

confidence: 99%

“…found two rare missense and one frameshift variant in JPH2 in three probands with HCM but their families were not studied or genotyped [ 28 ]. In 2016, Sabater-Molina showed segregation of the JPH2 p.(Glu85Lys) with dilated cardiomyopathy with or without left ventricular non-compaction cardiomyopathy (LVNC) features in a large family [ 25 ]. Furthermore, Quick et al have recently published JPH2 p.(Ala405Ser) variant in a single patient with basal septal hypertrophy and diastolic dysfunction [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

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Heterozygous junctophilin-2 (JPH2) p.(Thr161Lys) is a monogenic cause for HCM with heart failure

et al. 2018

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During the last two decades, mutations in sarcomere genes have found to comprise the most common cause for hypertrophic cardiomyopathy (HCM), but still significant number of patients with dominant HCM in the family are left without molecular genetic diagnosis. Next generation sequencing (NGS) does not only enable evaluation of established HCM genes but also candidate genes for cardiomyopathy are frequently tested which may lead to a situation where conclusive interpretation of the variant requires extensive family studies. We aimed to characterize the phenotype related to a variant in the junctophilin-2 (JPH2) gene, which is less known non-sarcomeric candidate gene. In addition, we did extensive review of the literature and databases about JPH2 variation in association with cardiac disease. We characterize nine Finnish index patients with HCM and heterozygous for JPH2 c.482C>A, p.(Thr161Lys) variant were included and segregation studies were performed. We identified 20 individuals affected with HCM with or without systolic heart failure and conduction abnormalities in the nine Finnish families with JPH2 p.(Thr161Lys) variant. We found 26 heterozygotes with the variant and penetrance was 71% by age 60 and 100% by age 80. Co-segregation of the variant with HCM phenotype was observed in six families. Main clinical features were left ventricular hypertrophy, arrhythmia vulnerability and conduction abnormalities including third degree AV-block. In some patients end-stage severe left ventricular heart failure with normal or mildly enlarged diastolic dimensions was detected. In conclusion, we propose that the heterozygous JPH2 p.(Thr161Lys) variant is a new Finnish mutation causing atypical HCM.

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Mutation in JPH2 cause dilated cardiomyopathy

Cited by 21 publications

References 6 publications

Genome-Wide Analysis Reveals Extensive Changes in LncRNAs during Skeletal Muscle Development in Hu Sheep

Genome-Wide Analysis Reveals Extensive Changes in LncRNAs during Skeletal Muscle Development in Hu Sheep

Junctophilin-2 gene therapy rescues heart failure by normalizing RyR2-mediated Ca2+ release

Heterozygous junctophilin-2 (JPH2) p.(Thr161Lys) is a monogenic cause for HCM with heart failure

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