Alternative titles; symbols
HGNC Approved Gene Symbol: JAG2
Cytogenetic location: 14q32.33 Genomic coordinates (GRCh38): 14:105,140,995-105,168,776 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 14q32.33 | Muscular dystrophy, limb-girdle, autosomal recessive 27 | 619566 | Autosomal recessive | 3 |
The JAG2 gene encodes a transmembrane protein that is a ligand for the Notch (see NOTCH1, 190198) family of transmembrane receptors that are critical for various cell fate decisions. Notch receptors are part of a conserved intercellular signaling mechanism that is essential for proper embryonic development in numerous metazoan organisms. Other Notch ligands have been identified, including Serrate (Ser) and Delta in Drosophila and JAG1 (601920) in vertebrates. Notch ligands interact directly with Notch receptors located on adjacent cells (trans-interaction) as well as on the same cell (cis-interaction) (summary by Luo et al., 1997 and Coppens et al., 2021).
By searching for human brain expressed sequence tags (ESTs) homologous to Drosophila and rat Serrate, Luo et al. (1997) identified a cDNA, which they called Jagged-2 (JAG2). The predicted 1,238-amino acid JAG2 protein has several recognizable motifs, including a signal peptide, 16 EGF-like repeats, a transmembrane domain, and a short cytoplasmic domain. The amino acid sequence of human JAG2 is 89% identical to that of rat Jag2. Northern blot analysis and in situ hybridization showed expression of Jag2 in various murine tissues. Immunohistochemistry revealed coexpression of Jag2 and Notch1 within murine fetal thymus and other murine fetal tissues. Coculture of fibroblasts expressing human JAG2 with murine C2C12 myoblasts inhibited myogenic differentiation. This effect was simulated by expression of constitutively active Notch1, suggesting that JAG2 engages the Notch1 pathway of signal transduction.
Gray et al. (1999) also cloned JAG2, which they called HJ2. Northern blot analysis revealed expression of a 5.3-kb JAG2 transcript in heart and skeletal muscle, with weaker expression in pancreas. In situ hybridization analysis indicated upregulated expression of JAG2 in squamous cell carcinoma.
Using Northern blot analysis, Deng et al. (2000) found that JAG2 was expressed at high levels in heart, skeletal muscle, and pancreas, and at low levels in brain and placenta. No expression was detected in lung, liver, and kidney.
Ikeuchi and Sisodia (2003) showed that the Notch ligands Delta1 (606582) and Jagged2 are subject to presenilin (PS1; 104311)-dependent, intramembranous gamma-secretase processing, resulting in the production of soluble intracellular derivatives. The authors also showed that the Delta1 intracellular domain (DICD) that is generated by the gamma-cleavage is transported into the nucleus and likely plays a role in transcriptional events. The authors proposed that the Jagged2 intracellular domain (JICD) would play a similar role.
Asnaghi et al. (2013) presented data suggesting that JAG2 can promote the growth and dissemination of uveal melanoma cells.
To disrupt Jagged signaling acutely in adult mammals, Lafkas et al. (2015) generated antibody antagonists that selectively target JAG1 and JAG2 and determined a crystal structure that explains selectivity. Lafkas et al. (2015) showed that acute Jagged blockade induces a rapid and near-complete loss of club cells, with a concomitant gain in ciliated cells, under homeostatic conditions without increased cell death or division. Fate analyses demonstrated a direct conversion of club cells to ciliated cells without proliferation, meeting a conservative definition of direct transdifferentiation. Jagged inhibition also reversed goblet cell metaplasia in a preclinical asthma model, providing a therapeutic foundation. Lafkas et al. (2015) concluded that their discovery that Jagged antagonism relieves a blockade of cell-to-cell conversion unveiled unexpected plasticity, and established a model for Notch regulation of transdifferentiation.
Deng et al. (2000) determined that the coding region of the JAG2 gene contains 26 exons. The promoter contains a TATA box and a CAC binding site. It has several potential transcription factor binding sites, including 3 for Sp1 (189906), 3 for OCT1 (POU2F1; 164175), 2 for E2F (189971), and 1 each for TFEB (600744) and NFKB (see 164011).
Using FISH, Gray et al. (1999) and Deng et al. (2000) mapped the JAG2 gene to chromosome 14q32. Lan et al. (1997) mapped the mouse Jag2 gene to the distal portion of chromosome 12 by interspecific backcross analysis.
In 23 patients from 13 unrelated families with autosomal recessive limb-girdle muscular dystrophy-27 (LGMDR27; 619566), Coppens et al. (2021) identified homozygous or compound heterozygous mutations in the JAG2 gene (see, e.g., 602570.0001-602570.0005). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. The families were gathered through international collaboration and gene matching programs; 6 families were consanguineous. There were 10 missense variants at highly conserved residues, 1 nonsense mutation, 2 frameshifts, and an in-frame deletion. In addition, 1 patient was compound heterozygous for a point mutation and a deletion of chromosome 14q32.33 encompassing the JAG2 gene. All variants were either absent from or present at a low frequency in only heterozygous state in the gnomAD database. Functional studies of the variants were not performed. Molecular modeling predicted that the mutations would cause a loss of function by decreasing JAG2 expression at the cell surface due to nonsense-mediated mRNA decay for the nonsense and frameshift mutations, or through protein misfolding and disturbances of inter- or intramolecular interactions for the missense mutations. RNA-seq analysis of skeletal muscle tissue derived from 2 unrelated patients showed altered expression of several genes compared to controls, including PAX7 (167410) and MYF5 (159990). Knockdown of Jag2 in murine C2C12 myoblast cells caused a reduction in Megf10 (612453), as well as downregulation of the expression of multiple genes in the Notch signaling pathway. MEGF10 is another transmembrane protein with similar involvement in the Notch pathway and is associated with an inherited muscle disease (614399). In Drosophila, the ortholog of JAG2 is serrate (Ser) and the ortholog of MEGF10 is draper (Drpr). Coppens et al. (2021) found that downregulation of Drpr in Ser-positive wing disc cells of Drosophila led to markedly diminished motor activity in adult flies, indicating that Ser cannot compensate for the loss of Drpr. The authors concluded that the disease mechanism is related to Notch pathway dysfunction.
Jiang et al. (1998) examined the in vivo role of the Jag2 gene by making a targeted mutation that removed a domain of the Jagged2 protein required for receptor interaction. Mice homozygous for this deletion died perinatally because of defects in craniofacial morphogenesis. The mutant homozygotes exhibited cleft palate and fusion of the tongue with the palatal shelves. They also exhibited syndactyly of the fore- and hindlimbs. The apical ectodermal ridge (AER) of the limb buds of the mutant homozygotes was hyperplastic, and Jiang et al. (1998) observed an expanded domain of Fgf8 (600483) expression in the AER. In the foot plates of the mutant homozygotes, both Bmp2 (112261) and Bmp7 (112267) expression and apoptotic interdigital cell death were reduced. Mutant homozygotes also displayed defects in thymic development, exhibiting altered thymic morphology and impaired differentiation of T cells of the gamma/delta lineage. These results demonstrated that Notch signaling mediated by Jag2 plays an essential role during limb, craniofacial, and thymic development in mice.
Lanford et al. (1999) showed that the genes encoding the receptor protein Notch1 and its ligand, Jag2, are expressed in alternating cell types in the developing sensory epithelium of the mammalian cochlea (the organ of Corti). The sensory epithelium contains 4 rows of mechanosensory hair cells: a single row of inner hair cells and 3 rows of outer hair cells. Each hair cell is separated from the next by an interceding supporting cell, forming an invariant and alternating mosaic that extends the length of the cochlear duct. Previous results had suggested that determination of cell fates in the cochlear mosaic occurs via inhibitory interactions between adjacent progenitor cells. Cells populating the cochlear epithelium appear to constitute a developmental equivalence group in which developing hair cells suppress differentiation in their immediate neighbors through lateral inhibition. Lanford et al. (1999) also found that genetic deletion of Jag2 results in a significant increase in sensory hair cells, presumably as the result of a decrease in Notch activation. These results provided direct evidence for Notch-mediated lateral inhibition in a mammalian system and supported a role for Notch in the development of the cochlear mosaic.
Richardson et al. (2009) showed that Irf6 (607199)/Jag2 doubly heterozygous mice displayed a fully penetrant intraoral epithelial adhesions, resulting in cleft palate. There was no evidence of direct interaction between Irf6 and Jag2, suggesting that the mechanism underlying the genetic interaction between Irf6 and Jag2 is the consequence of their combined effects on periderm formation, maintenance, and function. Notch1 and p63 (603273) expression patterns in Irf6/Jag2 doubly heterozygous mouse embryos suggested that Irf6 affects Jag2-Notch1 signaling during periderm maintenance.
In 2 sisters, born of consanguineous Moroccan parents (family BEL), with autosomal recessive limb-girdle muscular dystrophy-27 (LGMDR27; 619566), Coppens et al. (2021) identified a homozygous c.728C-A transversion (c.728C-A, NM_002226.5) in exon 5 of the JAG2 gene, resulting in an ala243-to-asp (A243D) substitution at a highly conserved residue in the linker sequence between the DSL domain and the first EGF repeat. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the gnomAD database. Functional studies of the variant were not performed.
In an 8-year-old child, born of consanguineous Iranian parents (family IRA), with autosomal recessive limb-girdle muscular dystrophy-27 (LGMDR27; 619566), Coppens et al. (2021) identified a homozygous c.490G-A transition (c.490G-A, NM_002226.5) in exon 4 of the JAG2 gene, resulting in a glu164-to-lys (E164K) substitution at a highly conserved residue in the N-terminal C2 domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was not present in the gnomAD database. Functional studies of the variant were not performed.
In 3 adult sibs, born of unrelated Polish parents (family POL), with autosomal recessive limb-girdle muscular dystrophy-27 (LGMDR27; 619566), Coppens et al. (2021) identified a homozygous c.2515G-A transition (c.2515G-A, NM_002226.5) in exon 21 of the JAG2 gene, resulting in a gly839-to-arg (G839R) substitution at a highly conserved residue in the EGF16 repeat domain. Two affected sisters from an unrelated family (US2) with the disorder were compound heterozygous for G839R and a c.221G-C transversion in exon 2, resulting in a cys74-to-ser substitution (C74S; 602570.0004) at a conserved residue in the N-terminal C2 domain. Finally, a 41-year-old affected man (family US1) was compound heterozygous for G839R and a deletion at chromosome 14q32.33 encompassing the JAG2 gene. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. G839R was found 6 times in only heterozygous state in the gnomAD database, whereas C74S was not present in gnomAD. There was some evidence of a common haplotype among those with the G839R variant. Functional studies of the variants were not performed.
For discussion of the c.221G-C transversion (c.221G-C, NM_002226.5) in the JAG2 gene, resulting in a cys74-to-ser substitution (C74S), that was found in compound heterozygous state in 2 sisters with autosomal recessive limb-girdle muscular dystrophy-27 (LGMDR27; 619566), by Coppens et al. (2021), see 602570.0003.
In 4 patients from 2 unrelated families (family UK, and family UAE, which was consanguineous) with autosomal recessive limb-girdle muscular dystrophy-27 (LGMDR27; 619566), Coppens et al. (2021) identified a homozygous c.2044C-T transition (c.2044C-T, NM_002226.5) in exon 16 of the JAG2 gene, resulting in a pro682-to-ser (P682S) substitution at a highly conserved residue in the EGF12 repeat domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families. It was present 63 times in only heterozygous state in the gnomAD database. There was evidence of a shared haplotype. Functional studies of the variant were not performed.
Asnaghi, L., Handa, J. T., Merbs, S. L., Harbour, J. W., Eberhart, C. G. A role for Jag2 in promoting uveal melanoma dissemination and growth. Invest. Ophthal. Vis. Sci. 54: 295-306, 2013. [PubMed: 23211831] [Full Text: https://doi.org/10.1167/iovs.12-10209]
Coppens, S., Barnard, A. M., Puusepp, S., Pajusalu, S., Ounap, K., Vargas-Franco, D., Bruels, C. C., Donkervoort, S., Pais, L., Chao, K. R., Goodrich, J. K., England, E. M., and 46 others. A form of muscular dystrophy associated with pathogenic variants in JAG2. Am. J. Hum. Genet. 108: 840-856, 2021. Note: Erratum: Am. J. Hum. Genet. 108: 1164 only, 2021. [PubMed: 33861953] [Full Text: https://doi.org/10.1016/j.ajhg.2021.03.020]
Deng, Y., Madan, A., Banta, A. B., Friedman, C., Trask, B. J., Hood, L., Li, L. Characterization, chromosomal localization, and the complete 30-kb DNA sequence of the human Jagged2 (JAG2) gene. Genomics 63: 133-138, 2000. [PubMed: 10662552] [Full Text: https://doi.org/10.1006/geno.1999.6045]
Gray, G. E., Mann, R. S., Mitsiadis, E., Henrique, D., Carcangiu, M.-L., Banks, A., Leiman, J., Ward, D., Ish-Horowitz, D., Artavanis-Tsakonas, S. Human ligands of the Notch receptor. Am. J. Path. 154: 785-794, 1999. [PubMed: 10079256] [Full Text: https://doi.org/10.1016/S0002-9440(10)65325-4]
Ikeuchi, T., Sisodia, S. S. The Notch ligands, Delta1 and Jagged2, are substrates for presenilin-dependent 'gamma-secretase' cleavage. J. Biol. Chem. 278: 7751-7754, 2003. [PubMed: 12551931] [Full Text: https://doi.org/10.1074/jbc.C200711200]
Jiang, R., Lan, Y., Chapman, H. D., Shawber, C., Norton, C. R., Serreze, D. V., Weinmaster, G., Gridley, T. Defects in limb, craniofacial, and thymic development in Jagged2 mutant mice. Genes Dev. 12: 1046-1057, 1998. [PubMed: 9531541] [Full Text: https://doi.org/10.1101/gad.12.7.1046]
Lafkas, D., Shelton, A., Chiu, C., de Leon Boenig, G., Chen, Y., Stawicki, S. S., Siltanen, C., Reichelt, M., Zhou, M., Wu, X., Eastham-Anderson, J., Moore, H., and 11 others. Therapeutic antibodies reveal Notch control of transdifferentiation in the adult lung. Nature 528: 127-131, 2015. [PubMed: 26580007] [Full Text: https://doi.org/10.1038/nature15715]
Lan, Y., Jiang, R., Shawber, C., Weinmaster, G., Gridley, T. The Jagged2 gene maps to chromosome 12 and is a candidate for the lgl and sm mutations. Mammalian Genome 8: 875-876, 1997. [PubMed: 9341252] [Full Text: https://doi.org/10.1007/s003359900642]
Lanford, P. J., Lan, Y., Jiang, R., Lindsell, C., Weinmaster, G., Gridley, T., Kelley, M. W. Notch signalling pathway mediates hair cell development in mammalian cochlea. Nature Genet. 21: 289-292, 1999. [PubMed: 10080181] [Full Text: https://doi.org/10.1038/6804]
Luo, B., Aster, J. C., Hasserjian, R. P., Kuo, F., Sklar, J. Isolation and functional analysis of a cDNA for human Jagged2, a gene encoding a ligand for the Notch1 receptor. Molec. Cell. Biol. 17: 6057-6067, 1997. [PubMed: 9315665] [Full Text: https://doi.org/10.1128/MCB.17.10.6057]
Richardson, R. J., Dixon, J., Jiang, R., Dixon, M. J. Integration of IRF6 and Jagged2 signalling is essential for controlling palatal adhesion and fusion competence. Hum. Molec. Genet. 18: 2632-2642, 2009. [PubMed: 19439425] [Full Text: https://doi.org/10.1093/hmg/ddp201]