Alternative titles; symbols
HGNC Approved Gene Symbol: JPH3
SNOMEDCT: 721228006;
Cytogenetic location: 16q24.2 Genomic coordinates (GRCh38) : 16:87,601,835-87,698,156 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16q24.2 | Huntington disease-like 2 | 606438 | Autosomal dominant | 3 |
The JPH3 gene encodes junctophilin-3, a member of a conserved family of proteins that are components of junctional complexes. 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. Junctophilins (JPs or JPHs) 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 (summary by Takeshima et al., 2000).
By screening genomic DNA libraries, Nishi et al. (2000) isolated the human JP1 (605266) and JP2 (605267) genes, and by screening a brain cDNA library, they isolated a cDNA encoding human JP3. The JP3 gene encodes a deduced 748-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 Northern and Western blot analyses, Nishi et al. (2003) found that Jp3 and Jp4 (JPH4; 619863) were coexpressed in mouse brain. Both genes were expressed in a neuron-specific manner during developmental stages. In hippocampal pyramidal neurons, both Jp3 and Jp4 showed somatodendritic localization.
Each JPH gene contains 5 exons (Nishi et al., 2000).
By FISH, Nishi et al. (2000) mapped the JP3 gene to 16q23-q24 and determined that the JP genes do not cluster on the human genome. Holmes et al. (2001), on the basis of sequence data provided by the Human Genome Project, localized the JPH3 gene to 16q24.3.
By microscopic analysis, Perni and Beam (2021) showed that heterologous expression of JPH3 or JPH4 induced formation of endoplasmic reticulum (ER)-plasma membrane (PM) junctions in tsA201 human embryonic kidney cells, with recruitment of the neuronal, high voltage-activated calcium channels CaV1.2 (CACNA1C; 114205), CaV2.1 (CACNA1A; 601011), and CaV2.2 (CACNA1B; 601012), but not the low voltage-activated channel CaV3.1 (CACNA1G; 604065), to the junctions. Expression of JPH3 and JPH4 significantly slowed inactivation of CaV2.1 and CaV2.2, but this ability of JPH3 and JPH4 was independent of formation of ER-PM junctions and rather was a consequence of direct interaction between the channels and JPHs. JPH3 and JPH4 also recruited ryanodine receptors to the ER-PM junctions. However, JPH3 was substantially more effective than JPH4, as JPH3 recruited RyR1 (180901), RYR2 (180902), and RYR3 (180903), whereas JPH4 only recruited RYR3. RYR3 moderately colocalized at junctions with JPH4, whereas RYR1 and RYR2 did not. In contrast, RYR1 and RYR3 strongly colocalized with JPH3, and RYR2 moderately colocalized with it. The cytoplasmic divergent region adjacent to the ER transmembrane segment appeared to be responsible for differential recruitment of ryanodine receptors by JPH3 and JPH4. Mutation analysis showed that JPH3 bound to cytoplasmic domain constructs of RYR1 and RYR3, but not of RYR2.
Margolis et al. (2001) described a disorder termed Huntington disease-like-2 (HDL2; 606438) segregating in an autosomal dominant pattern in a large pedigree with an unidentified CAG/CTG expansion. Holmes et al. (2001) reported the cloning of this expansion and its localization to a variably spliced exon of JPH3, a gene involved in the formation of junctional membrane structures. All 10 affected individuals tested had a repeat expansion, ranging in size from 51 to 57 triplets, whereas 3 unaffected individuals had 2 unexpanded alleles. The variability of the length of the expanded repeat among sibs from 3 different sibships indicated that the expanded allele is unstable in vertical transmission. There was no apparent correlation between repeat size and age of onset, but the range of repeat length among family members was narrow. The index family was African American; Holmes et al. (2001) detected HDL2-related repeat expansions in 4 African American individuals from the southeastern United States, each of whom had a familial Huntington disease-like disorder and had tested negative for the Huntington disease mutation. They demonstrated that the CTG repeat is localized 760 nucleotides 3-prime to the end of exon 1. At least 4 lines of evidence suggested that the CTG repeat is contained within an alternatively spliced exon (termed 2A) of the JPH3 gene that has multiple splice acceptor sites.
Among 74 patients with an HD-like phenotype but without CAG repeat expansions in the IT15 gene, Stevanin et al. (2002) identified 1 patient with a pure uninterrupted 50 CAG/CTG repeat in the JPH3 gene. The patient was a 44-year-old Moroccan woman with subcortical dementia, mild choreic movements, and atrophy of the cerebral cortex.
In 3 members of a family with HLD2, originally reported by Walker et al. (2002) as having choreoacanthocytosis, Walker et al. (2003) identified trinucleotide repeat expansions of 51, 58, and 57 triplets in the JPH3 gene. The authors identified affected members of 2 other families with trinucleotide repeats in the JPH3 gene.
Moriguchi et al. (2006) found that Jp3 and Jp4 double-knockout (DKO) mice showed severe growth retardation and lethality 3 to 4 weeks after birth due to a feeding defect likely caused by defective saliva secretion. Most mature DKO mice that survived were infertile. In behavioral tests, DKO mice displayed foot-clasping reflex and impaired exploratory activity and memory. DKO brain had no major pathologic defects, with normal size and morphology, but apamin-sensitive afterhyperpolarization (AHP) was completely absent in hippocampal neurons at any resting potentials. In wildtype hippocampal neurons, activation of small-conductance Ca(2+)-activated K+ channels responsible for AHP required ER Ca(2+) release through ryanodine receptors triggered by NMDA receptor (see 138249)-mediated Ca(2+) influx. The authors proposed that functional communication between NMDA receptors, ryanodine receptors, and small-conductance Ca(2+)-activated K+ channels was disconnected in DKO neurons lacking AHP due to disassembly of junctional membrane complexes. Moreover, hippocampal plasticity was impaired in DKO mice, as DKO neurons showed impaired long-term potentiation and hyperactivation of Ca(2+)/calmodulin-dependent protein kinase II (see 114078).
In affected members of an African American family with Huntington disease-like-2 (HDL2; 606438), Holmes et al. (2001) demonstrated a CAG/CTG repeat expansion of about 40 or more triplets in an alternatively spliced exon of the JPH3 gene. Holmes et al. (2001) found the same mutation in 4 other African American individuals from the southeastern United States, each of whom had a familial Huntington disease-like disorder and had tested negative for the Huntington disease mutation in the IT15 gene (613004).
Among 74 patients with an HD-like phenotype but without CAG repeat expansions in the IT15 gene, Stevanin et al. (2002) identified 1 patient with a pure uninterrupted 50 CAG/CTG repeat in the JPH3 gene. The patient was a 44-year-old Moroccan woman with subcortical dementia, mild choreic movements, and atrophy of the cerebral cortex.
In 3 members of a family with HLD2, originally reported by Walker et al. (2002) as having choreoacanthocytosis, Walker et al. (2003) identified trinucleotide repeat expansions of 51, 58, and 57 triplets in the JPH3 gene. The authors identified affected members of 2 other families with trinucleotide repeats in the JPH3 gene.
Holmes, S. E., O'Hearn, E., Rosenblatt, A., Callahan, C., Hwang, H. S., Ingersoll-Ashworth, R. G., Fleisher, A., Stevanin, G., Brice, A., Potter, N. T., Ross, C. A., Margolis, R. L. A repeat expansion in the gene encoding junctophilin-3 is associated with Huntington disease-like 2. Nature Genet. 29: 377-378, 2001. Note: Erratum: Nature Genet. 30: 123 only, 2002. [PubMed: 11694876] [Full Text: https://doi.org/10.1038/ng760]
Margolis, R. L., O'Hearn, E., Rosenblatt, A., Willour, V., Holmes, S. E., Franz, M. L., Callahan, C., Hwang, H. S., Troncoso, J. C., Ross, C. A. A disorder similar to Huntington's disease is associated with a novel CAG repeat expansion. Ann. Neurol. 50: 373-380, 2001. [PubMed: 11761463] [Full Text: https://doi.org/10.1002/ana.1312]
Moriguchi, S., Nishi, M., Komazaki, S., Sakagami, H., Miyazaki, T., Masumiya, H., Saito, S., Watanabe, M., Kondo, H., Yawo, H., Fukunaga, K., Takeshima, H. Functional uncoupling between Ca(2+) release and afterhyperpolarization in mutant hippocampal neurons lacking junctophilins. Proc. Nat. Acad. Sci. 103: 10811-10816, 2006. [PubMed: 16809425] [Full Text: https://doi.org/10.1073/pnas.0509863103]
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]
Nishi, M., Sakagami, H., Komazaki, S., Kondo, H., Takeshima, H. Coexpression of junctophilin type 3 and type 4 in brain. Molec. Brain Res. 118: 102-110, 2003. [PubMed: 14559359] [Full Text: https://doi.org/10.1016/s0169-328x(03)00341-3]
Perni, S., Beam, K. Neuronal junctophilins recruit specific CaV and RyR isoforms to ER-PM junctions and functionally alter CaV2.1 and CaV2.2. eLife 10: e64249, 2021. [PubMed: 33769283] [Full Text: https://doi.org/10.7554/eLife.64249]
Stevanin, G., Camuzat, A., Holmes, S. E., Julien, C., Sahloul, R., Dode, C., Hahn-Barma, V., Ross, C. A., Margolis, R. L., Durr, A., Brice, A. CAG/CTG repeat expansions at the Huntington's disease-like 2 locus are rare in Huntington's disease patients. Neurology 58: 965-967, 2002. [PubMed: 11914418] [Full Text: https://doi.org/10.1212/wnl.58.6.965]
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]
Walker, R. H., Morgello, S., Davidoff-Feldman, B., Melnick, A., Walsh, M. J., Shashidharan, P., Brin, M. F. Autosomal dominant chorea-acanthocytosis with polyglutamine-containing neuronal inclusions. Neurology 58: 1031-1037, 2002. [PubMed: 11940688] [Full Text: https://doi.org/10.1212/wnl.58.7.1031]
Walker, R. H., Rasmussen, A., Rudnicki, D., Holmes, S. E., Alonso, E., Matsuura, T., Ashizawa, T., Davidoff-Feldman, B., Margolis, R. L. Huntington's disease-like 2 can present as chorea-acanthocytosis. Neurology 61: 1002-1004, 2003. [PubMed: 14557581] [Full Text: https://doi.org/10.1212/01.wnl.0000085866.68470.6d]