Alternative titles; symbols
HGNC Approved Gene Symbol: JPH2
Cytogenetic location: 20q13.12 Genomic coordinates (GRCh38): 20:44,106,590-44,187,188 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 20q13.12 | Cardiomyopathy, dilated, 2E | 619492 | Autosomal recessive | 3 |
| Cardiomyopathy, hypertrophic, 17 | 613873 | Autosomal dominant | 3 |
Junctional complexes between the plasma membrane (PM) and endoplasmic/sarcoplasmic reticulum (ER/SR) are a common feature of all excitable cell types and mediate cross talk between cell surface and intracellular ion channels. Takeshima et al. (2000) identified the junctophilins (JPs), a conserved family of proteins that are components of the junctional complexes. JPs are composed of a C-terminal hydrophobic segment spanning the ER/SR membrane and a remaining cytoplasmic domain that shows specific affinity for the PM. In mouse, there are at least 3 JP subtypes: Jp1, Jp2, and Jp3.
By screening genomic DNA libraries, Nishi et al. (2000) isolated the human JP1 (JPH1; 605266) and JP2 genes, and by screening a brain cDNA library, they isolated a cDNA encoding human JP3 (JPH3; 605268). The JP2 gene encodes a deduced 696-amino acid protein. The human JPs share an overall sequence identity of 39%, and they share characteristic structural features with their rabbit and mouse counterparts. RNA blot hybridization indicated that the tissue-specific expression patterns of the JP genes in human are essentially the same as those in mouse; JP1 was expressed as a 4.5-kb transcript in skeletal muscle and at low levels in heart, JP2 was expressed as a 4.1-kb transcript in heart and skeletal muscle, and JP3 was expressed as a 4.6-kb transcript in brain.
Using gradient and Western blot analyses, Minamisawa et al. (2004) showed that mouse Jp2 localized to low-density membrane fractions in mouse ventricular myocytes.
Matsushita et al. (2007) noted that the JPH2 protein is composed of 6 predicted domains: MORN (membrane occupation and recognition nexus) motif region I (MORN1), joining region, MORN2 motif, putative alpha-helical region, divergent region, and membrane-spanning region.
Nishi et al. (2000) determined that the JPH2 gene contains 5 exons, similar to JPH1 and JPH3.
By FISH, Nishi et al. (2000) mapped the JPH2 gene to chromosome 20q12 and determined that the JPH genes do not cluster on the human genome.
Stumpf (2021) mapped the JPH2 gene to chromosome 20q13.12 based on an alignment of the JPH2 sequence (GenBank BC172751) with the genomic sequence (GRCh38).
Takeshima et al. (2000) showed that Jp2 is abundantly expressed in mouse heart, and mutant mice lacking Jp2 exhibited embryonic lethality. Cardiac myocytes from the mutant mice showed deficiency of the junctional membrane complexes and abnormal calcium transients. These results suggested that JPs are important components of junctional membrane complexes.
By immunoprecipitation and immunoblot analyses, Minamisawa et al. (2004) showed that Jp2 interacted and colocalized with caveolin-3 (CAV3; 601253) in membranes of mouse ventricular myocytes. Expression of Jp2 was upregulated during normal development but downregulated in mouse models of hypertrophic and dilated cardiomyopathy. The results suggested that expression levels of Jp2 are likely associated with normal development of junctional membrane complexes and impaired Ca(2+)-induced Ca(2+) release in heart.
After cardiac stress, JP2 is cleaved by the calcium ion-dependent protease calpain (see 114220), which disrupts the excitation-contraction (E-C) coupling ultrastructural machinery and drives heart failure progression. Guo et al. (2018) found that stress-induced proteolysis of JP2 liberates an N-terminal fragment (JP2NT) that translocates to the nucleus, binds to genomic DNA, and controls expression of a spectrum of genes in cardiomyocytes. Transgenic overexpression of JP2NT in mice modifies the transcriptional profile, resulting in attenuated pathologic remodeling in response to cardiac stress. Conversely, loss of nuclear JP2NT function accelerates stress-induced development of hypertrophy and heart failure in mutant mice. Guo et al. (2018) concluded that their data revealed a self-protective mechanism in failing cardiomyocytes that transduce mechanical information (E-C uncoupling) into salutary transcriptional reprogramming in the stressed heart.
Hypertrophic Cardiomyopathy 17
In 223 unrelated patients with hypertrophic cardiomyopathy (see CMH17, 613873), who were negative for mutation in 8 myofilament-associated genes and 5 Z disc-associated genes, Landstrom et al. (2007) analyzed the candidate gene JPH2 and identified heterozygosity for 3 different missense mutations in 3 probands (605267.0001-605267.0003, respectively). Functional analysis demonstrated that the mutations caused protein reorganization of JPH2, perturbations in intracellular calcium signaling, and marked cardiomyocyte hyperplasia.
Dilated Cardiomyopathy 2E
From a cohort of 66 patients with childhood-onset cardiomyopathy who presented to the single center in Finland performing cardiac transplantations, Vasilescu et al. (2018) identified a 22.5-year-old woman with dilated cardiomyopathy (CMD2E; 619492) who was homozygous for a nonsense mutation in the JPH2 gene (Q428X; 605267.0005). The variant segregated fully with disease in the proband's family.
From a cohort of 823 clinical whole-exome sequencing (WES) referrals from Iran, Jones et al. (2019) identified 2 consanguineous families with neonatal dilated cardiomyopathy associated with death in early childhood, caused by the same 1-bp duplication in the JPH2 gene (605267.0006). The mutation segregated with disease in both families, who shared an identical haplotype containing the JPH2 variant, indicating a founder effect. To characterize ethnicity-dependent genetic variability in the JPH2 gene, the authors analyzed the gnomAD, Greater Middle East (GME) Variome, and Iranome databases, compared to WES referral tests and a cohort of patients with hypertrophic cardiomyopathy (see 192600). Worldwide, 1.45% of healthy individuals hosted a rare JPH2 variant, with a significantly higher proportion (4.45%) among GME individuals. Loss-of-function (LOF) variants were rare overall (0.04%) yet were most prevalent in GME individuals (0.21%), and this increased prevalence of LOF variants in GME individuals was corroborated in region-specific clinical WES cohorts. The authors concluded that there are ethnicity-specific differences in JPH2 rare variants, with GME individuals being at higher risk of homozygosity for LOF variants.
To circumvent embryonic lethality associated with germline Jph2 knockout in mice, van Oort et al. (2011) used short hairpin RNA-mediated interference to generate mutant mice with conditionally reduced Jph2 protein levels. Cardiac-specific Jph2 knockdown resulted in impaired cardiac contractility, which caused heart failure and increased mortality. Jph2 deficiency resulted in loss of excitation-contraction coupling gain, precipitated by a reduction in the number of junctional membrane complexes and increased variability in the plasmalemma-sarcoplasmic reticulum distance. Noting that loss of Jph2 had profound effects on Ca(2+) release channel inactivation, the authors suggested a role for JPH2 in regulating intracellular Ca(2+) release channels in cardiac myocytes.
In a 40-year-old man who was diagnosed at age 27 years with hypertrophic cardiomyopathy (CMH17; 613873), Landstrom et al. (2007) identified heterozygosity for a mutation in exon 1 of the JPH2 gene, resulting in a ser101-to-arg (S101R) substitution in the conserved MORN motif. The mutation was not identified in 1,000 Caucasian reference alleles. Studies in transfected H9c2 cardiomyocytes showed an altered localization pattern with respect to the sarcoplasmic reticulum (SR). Analysis of transfected HL-1 cardiomyocytes indicated decreased spontaneous calcium release from the SR, suggesting that excitation-contraction process was disrupted in cells expressing S101R. The patient, who had dyspnea and had undergone placement of an implantable cardioverter-defibrillator, had a family history of CMH, with 3 first-degree affected relatives and 1 second-degree relative, all of whom declined to participate in the study.
In a 33-year-old man who was diagnosed at age 24 years with hypertrophic cardiomyopathy (CMH17; 613873), Landstrom et al. (2007) identified heterozygosity for a mutation in exon 2 of the JPH2 gene, resulting in a tyr141-to-his (Y141H) substitution at a conserved residue. The mutation was not identified in 1,000 Caucasian reference alleles. Studies in transfected H9c2 cardiomyocytes showed an altered localization pattern with respect to the sarcoplasmic reticulum (SR) and significant hypertrophy (2- to 3-fold) compared to wildtype. Analysis of transfected HL-1 cardiomyocytes indicated decreased spontaneous calcium release from the SR, suggesting that excitation-contraction process was disrupted in cells expressing Y141H. At presentation, the patient had dyspnea, palpitations, angina, and a non-Q-wave myocardial infarction; he underwent placement of a pacemaker and an implantable cardioverter-defibrillator. There was no family history of CMH or sudden cardiac death.
In a 58-year-old female who was diagnosed at 30 years of age with hypertrophic cardiomyopathy (CMH17; 613873), Landstrom et al. (2007) identified heterozygosity for a mutation in exon 2 of the JPH2 gene, resulting in a ser165-to-phe (S165F) substitution at a conserved residue. The mutation was not identified in 1,000 Caucasian reference alleles. Studies in transfected H9c2 cardiomyocytes showed an altered localization pattern with respect to the sarcoplasmic reticulum (SR) and significant hypertrophy (2- to 3-fold) compared to wildtype. Analysis of transfected HL-1 cardiomyocytes indicated decreased spontaneous calcium release from the SR, suggesting that excitation-contraction process was disrupted in cells expressing S165F. At presentation, the patient had dyspnea and subacute bacterial endocarditis; she underwent surgical myectomy. There was no family history of CMH or sudden cardiac death.
This variant, formerly titled CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC 17, has been reclassified based on the findings of Manrai et al. (2016) and Hamosh (2016).
Matsushita et al. (2007) analyzed the candidate gene JPH2 in 148 Japanese probands with CMH and 48 affected family members, as well as 32 patients with dilated cardiomyopathy (CMD; see 115200) and 8 patients with restrictive cardiomyopathy (RCM; see 115210). In 4 Japanese probands with hypertrophic cardiomyopathy (CMH17; 613873), Matsushita et al. (2007) identified heterozygosity for a 1306C-T transition in exon 4 of the JPH2 gene, resulting in a gly505-to-ser (G505S) substitution in the divergent region. The G505S mutation was not found in CMD or RCM patients or in 236 Japanese controls. One of the patients, who was diagnosed with CMH at 14 years of age, had a mother who was diagnosed at 40 years of age and also carried the G505S mutation. His healthy father did not carry the mutation, and a younger sister who had died suddenly at 3 years of age could not be examined. Another proband, who was diagnosed with CMH at 33 years of age, had a family history of CMH involving her grandfather, father, and the father's sibs, who were not available for genetic analysis. Analysis of 15 known CMH-associated genes in the 4 probands carrying the G505S mutation in JPH2 revealed that the female proband also carried 2 missense mutations in the MYH7 gene (see, e.g., 160760.0016). Her newborn son, who had no signs of CMH on echocardiography at 1 day of age, carried both the JPH2 G505S mutation and 1 of the MYH7 mutations. Matsushita et al. (2007) suggested that mutations in both JPH2 and MYH7 could be associated with the pathogenesis of CMH in this proband.
Manrai et al. (2016) found that the G505S variant in JPH2 has an allele frequency of 0.8% in white Americans and 2.9% in black Americans in the NHLBI Exome Sequencing Project data set. Manrai et al. (2016) classified this variant as benign based on its high frequency in control populations and on patient and functional data. Hamosh (2016) observed that the G505S variant had an allele frequency of 7.3% in South Asians in the ExAC database on September 20, 2016.
In a 22.5-year-old Finnish woman (P10) who was diagnosed with dilated cardiomyopathy (CMD2E; 619492) at 3 years of age and underwent cardiac transplantation at age 4, Vasilescu et al. (2018) identified homozygosity for a c.1282C-T transition in the JPH2 gene, resulting in a gln428-to-ter (Q428X) substitution. Her unaffected parents and 2 unaffected sibs were heterozygous for the mutation. Functional studies of the variant or of patient cells were not performed. The authors' criteria for causative recessive variants were a minor allele frequency of less than or equal to 0.01 in the ExAC, gnomAD, and SISu databases, and presence only in heterozygosity; the exact frequency for this variant was not published.
In 2 consanguineous Iranian families with neonatal dilated cardiomyopathy (CMD2E; 619492), Jones et al. (2019) identified homozygosity for a 1-bp duplication (c.1920dupT, NM_020433) in the JPH2 gene, predicted to cause a premature termination codon (glu641-to-ter; E641X) within the divergent region. The mutation segregated with disease in both families: in family 1, the proband was homozygous for the variant, which was present in heterozygosity in 11 unaffected relatives, including his first-cousin parents; in family 2, DNA was unavailable from the 2 deceased brothers, but their unaffected consanguineous parents were each heterozygous for the variant, as were 2 more unaffected relatives. The families were not known to be related, but both were of the Lor ethnic background from southwest Iran and they shared an identical haplotype containing the JPH2 variant, indicating a founder effect. Functional studies of the variant or of patient cells were not performed. The variant was absent from 299,100 reference alleles derived from healthy individuals.
Guo, A., Wang, Y., Chen, B., Wang, Y., Yuan, J., Zhang, L., Hall, D., Wu, J., Shi, Y., Zhu, Q., Chen, C., Thiel, W. H., and 11 others. E-C coupling structural protein junctophilin-2 encodes a stress-adaptive transcription regulator. Science 362: eaan3303, 2018. Note: Electronic Article. [PubMed: 30409805] [Full Text: https://doi.org/10.1126/science.aan3303]
Hamosh, A. Personal Communication. Baltimore, Md. 09/20/2016.
Jones, E. G., Mazaheri, N., Maroofian, R., Zamani, M., Seifi, T., Sedaghat, A., Shariati, G., Jamshidi, Y., Allen, H. D., Wehrens, X. H. T., Galehdari, H., Landstrom, A. P. 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. Sci. Rep. 9: 9038, 2019. [PubMed: 31227780] [Full Text: https://doi.org/10.1038/s41598-019-44987-6]
Landstrom, A. P., Weisleder, N., Batalden, K. B., Bos, J. M., Tester, D. J., Ommen, S. R., Wehrens, X. H. T., Claycomb, W. C., Ko, J.-K., Hwang, M., Pan, Z., Ma, J., Ackerman, M. J. Mutations in JPH2-encoded junctophilin-2 associated with hypertrophic cardiomyopathy in humans. J. Molec. Cell. Cardiol. 42: 1026-1035, 2007. [PubMed: 17509612] [Full Text: https://doi.org/10.1016/j.yjmcc.2007.04.006]
Manrai, A. K., Funke, B. H., Rehm, H. L., Olesen, M. S., Maron, B. A., Szolovits, P., Margulies, D. M., Loscalzo, J., Kohane, I. S. Genetic misdiagnoses and the potential for health disparities. New Eng. J. Med. 375: 655-665, 2016. [PubMed: 27532831] [Full Text: https://doi.org/10.1056/NEJMsa1507092]
Matsushita, Y., Furukawa, T., Kasanuki, H., Nishibatake, M., Kurihara, Y., Ikeda, A., Kamatani, N., Takeshima, H., Matsuoka, R. Mutation of junctophilin type 2 associated with hypertrophic cardiomyopathy. J. Hum. Genet. 52: 543-548, 2007. [PubMed: 17476457] [Full Text: https://doi.org/10.1007/s10038-007-0149-y]
Minamisawa, S., Oshikawa, J., Takeshima, H., Hoshijima, M., Wang, Y., Chien, K. R., Ishikawa, Y., Matsuoka, R. Junctophilin type 2 is associated with caveolin-3 and is down-regulated in the hypertrophic and dilated cardiomyopathies. Biochem. Biophys. Res. Commun. 325: 852-856, 2004. [PubMed: 15541368] [Full Text: https://doi.org/10.1016/j.bbrc.2004.10.107]
Nishi, M., Mizushima, A., Nakagawara, K., Takeshima, H. Characterization of human junctophilin subtype genes. Biochem. Biophys. Res. Commun. 273: 920-927, 2000. [PubMed: 10891348] [Full Text: https://doi.org/10.1006/bbrc.2000.3011]
Stumpf, A. M. Personal Communication. Baltimore, Md. 08/18/2021.
Takeshima, H., Komazaki, S., Nishi, M., Iino, M., Kangawa, K. Junctophilins: a novel family of junctional membrane complex proteins. Molec. Cell 6: 11-22, 2000. [PubMed: 10949023] [Full Text: https://doi.org/10.1016/s1097-2765(00)00003-4]
van Oort, R. J., Garbino, A., Wang, W., Dixit, S. S., Landstrom, A. P., Gaur, N., De Almeida, A. C., Skapura, D. G., Rudy, Y., Burns, A. R., Ackerman, M. J., Wehrens, X. H. T. Disrupted junctional membrane complexes and hyperactive ryanodine receptors after acute junctophilin knockdown in mice. Circulation 123: 979-988, 2011. [PubMed: 21339484] [Full Text: https://doi.org/10.1161/CIRCULATIONAHA.110.006437]
Vasilescu, C., Ojala, T. H., Brilhante, V., Ojanen, S., Hinterding, H. M., Palin, E., Alastalo, T.-P., Koskenvuo, J., Hiippala, A., Jokinen, E., Jahnukainen, T., Lohi, J., Pihkala, J., Tyni, T. A., Carroll, C. J., Suomalainen, A. Genetic basis of severe childhood-onset cardiomyopathies. J. Am. Coll. Cardiol. 72: 2324-2338, 2018. [PubMed: 30384889] [Full Text: https://doi.org/10.1016/j.jacc.2018.08.2171]