Alternative titles; symbols
HGNC Approved Gene Symbol: OSMR
Cytogenetic location: 5p13.1 Genomic coordinates (GRCh38) : 5:38,846,012-38,945,579 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5p13.1 | Amyloidosis, primary localized cutaneous, 1 | 105250 | Autosomal dominant | 3 |
Oncostatin M (OSM; 165095) is a member of the IL6 (147620) family of cytokines. Functional receptors for IL6 family cytokines are multisubunit complexes involving members of the hematopoietin receptor superfamily. Many IL6 cytokines utilize gp130 (IL6ST; 600694) as a common receptor subunit. OSM binds to the gp130 receptor subunit and, in association with leukemia inhibitory factor receptor (LIFR; 151443), induces a proliferative response in permissive cells. Mosley et al. (1996) used degenerate PCR to clone a novel hematopoietin receptor which they called the oncostatin M-specific receptor beta subunit (OSMR-beta). Sequencing revealed that this gene encodes a 979-amino acid protein containing characteristic motifs of the hematopoietin receptor family.
Mosley et al. (1996) found that IL3 (147740)-dependent murine pre-B cells coexpressing gp130 and OSMR-beta showed a proliferative response after OSM stimulation, but they showed no response to LIF.
Dillon et al. (2004) demonstrated that OSMR and IL31RA (609510) form the heterodimeric receptor through which IL31 (609509) signals. Expression of IL31RA and OSMR mRNA was induced in activated monocytes, and both mRNAs were constitutively expressed in epithelial cells Expression of IL31RA was upregulated in monocytes after stimulation with IFNG (147570), and OSMR expression was upregulated with lipopolysaccharide (LPS) treatment. Treatment with LPS plus IFNG upregulated both receptors.
Glioblastomas (see 137800) arise from astrocytes and their precursors, neural stem cells, and are frequently associated with activating mutations of EGFR (131550). The most common activating mutation of EGFR in glioblastoma is deletion of exons 2 through 7, which generates a constitutively active EGFR, termed EGFRvIII, that induces phosphorylation of STAT3 (102582) to drive tumorigenesis. Using RNA sequencing analysis, Western blot analysis, and deletion and knockdown experiments, Jahani-Asl et al. (2016) found that OSMR was highly expressed in a STAT3-dependent manner in EGFRvIII-expressing human brain tumor stem cells (BTSCs) and mouse astrocytes compared with controls. Chromatin immunoprecipitation and sequencing showed that STAT3 occupied the promoter of the OSMR gene. There was significant overlap among OSMR-, STAT3-, and EGFRvIII-dependent target genes. Immunohistochemical analysis demonstrated that OSMR and EGFRvIII formed a coreceptor complex at the cell membrane, and gp130 and wildtype EGFR were not required for the interaction. OSM signaling induced phosphorylation and activation of EGFR, leading to EGFR-OSMR interaction. Knockdown of OSMR inhibited proliferation of BTSCs and astrocytes. Furthermore, knockdown of Osmr suppressed tumor growth in SCID mice injected with EgfrvIII-expressing astrocytes or BTSCs. Jahani-Asl et al. (2016) concluded that OSMR is a cell surface receptor that defines a feed-forward mechanism with EGFRvIII and STAT3 in glioblastoma pathogenesis.
By candidate gene analysis in a 5p13.1-q11.2 region of linkage identified in families with primary localized cutaneous amyloidosis (PLCA1; 105250), Arita et al. (2008) identified missense mutations in the OSMR gene in 3 families (601743.0001-601743.0002). OSMR-beta is a component of the OSM type II receptor and the interleukin-31 receptor (IL31RA; 609510). Arita et al. (2008) found that PLCA keratinocytes showed reduced activation of Jak/Stat, MAPK, and p13K/Akt pathways after OSM or IL31 cytokine stimulation. The 2 pathogenic amino acid substitutions found by Arita et al. (2008) were located within the extracellular fibronectin type III-like (FnIII) domains, regions critical for receptor dimerization and function. OSM and IL31 (609509) have been implicated in keratinocyte cell proliferation, differentiation, apoptosis, and inflammation. Arita et al. (2008) pointed to this as the first demonstration of human germline mutations in this cytokine receptor complex and suggested that it provides new insight into mechanisms of skin itching.
By whole-exome sequencing of the OSMR gene in Taiwanese patients with PLCA mapping to chromosome 5, Lin et al. (2010) identified 3 novel heterozygous mutations (601743.0003-601743.0005). In 1 Taiwanese family they identified a heterozygous mutation in the IL31RA gene (609510.0001), which occurred in a fnIII domain as observed in the OSMR mutations.
In an extensively affected Brazilian pedigree with primary localized cutaneous amyloidosis (105250), Arita et al. (2008) identified a heterozygous 2072T-C transition in the OSMR gene resulting in an ile691-to-thr substitution (I691T) in all affected but no unaffected members.
In affected members of 2 white families with primary localized cutaneous amyloidosis (105250), Arita et al. (2008) found an 1853G-C transversion in the OSMR gene that resulted in a gly618-to-ala substitution (G618A). Microsatellite analysis around the OSMR gene indicated that the 2 families probably shared a common British ancestry.
In affected members of a Taiwanese family segregating primary localized cutaneous amyloidosis (105250), Lin et al. (2010) identified a heterozygous 1940A-T transversion in the OSMR gene, resulting in an asp647-to-val (D647V) substitution in the fnIII domain. The mutation was not found in 142 control subjects from Taiwan or in over 250 control chromosomes from other populations.
In affected members of 6 Taiwanese families segregating primary localized cutaneous amyloidosis (105250), Lin et al. (2010) identified a heterozygous 2081C-T transition in the OSMR gene, resulting in a pro694-to-leu (P694L) substitution in the fnIII domain. The mutation was also detected in 2 Taiwanese sporadic cases. Five of the 6 families and the 2 sporadic cases carried the same associated haplotype. The mutation was not found in 142 control subjects from Taiwan or in over 250 control chromosomes from other populations.
In affected members of 3 Taiwanese families segregating primary localized cutaneous amyloidosis (105250), Lin et al. (2010) identified a heterozygous 2090A-C transversion in the OSMR gene, resulting in a lys697-to-thr substitution in the fnIII domain. The mutation was not found in 142 control subjects from Taiwan or in over 250 control chromosomes from other populations.
Arita, K., South, A. P., Hans-Filho, G., Sakuma, T. H., Lai-Cheong, J., Clements, S., Odashiro, M., Odashiro, D. N., Hans-Neto, G., Hans, N. R., Holder, M. V., Bhogal, B. S., Hartshorne, S. T., Akiyama, M., Shimizu, H., McGrath, J. A. Oncostatin M receptor-beta mutations underlie familial primary localized cutaneous amyloidosis. Am. J. Hum. Genet. 82: 73-80, 2008. [PubMed: 18179886] [Full Text: https://doi.org/10.1016/j.ajhg.2007.09.002]
Dillon, S. R., Sprecher, C., Hammond, A., Bilsborough, J., Rosenfeld-Franklin, M., Presnell, S. R., Haugen, H. S., Maurer, M., Harder, B., Johnston, J., Bort, S., Mudri, S., and 18 others. Interleukin 31, a cytokine produced by activated T cells, induces dermatitis in mice. Nature Immun. 5: 752-760, 2004. Note: Erratum: Nature Immun. 6: 114 only, 2005. [PubMed: 15184896] [Full Text: https://doi.org/10.1038/ni1084]
Jahani-Asl, A., Yin, H., Soleimani, V. D., Haque, T., Luchman, H. A., Chang, N. C., Sincennes, M.-C., Puram, S. V., Scott, A. M., Lorimer, I. A. J., Perkins, T. J., Ligon, K. L., Weiss, S., Rudnicki, M. A., Bonni, A. Control of glioblastoma tumorigenesis by feed-forward cytokine signaling. Nature Neurosci. 19: 798-806, 2016. [PubMed: 27110918] [Full Text: https://doi.org/10.1038/nn.4295]
Lin, M.-W., Lee, D.-D., Liu, T.-T., Lin, Y.-F., Chen, S.-Y., Huang, C.-C., Weng, H.-Y., Liu, Y.-F., Tanaka, A., Arita, K., Lai-Cheong, J., Palisson, F., Chang, Y.-T., Wong, C.-K., Matsuura, I., McGrath, J. A., Tsai, S.-F. Novel IL31RA gene mutation and ancestral OSMR mutant allele in familial primary cutaneous amyloidosis. Europ. J. Hum. Genet. 18: 26-32, 2010. [PubMed: 19690585] [Full Text: https://doi.org/10.1038/ejhg.2009.135]
Mosley, B., De Imus, C., Friend, D., Boiani, N., Thoma, B., Park, L. S., Cosman, D. Dual oncostatin M (OSM) receptors. J. Biol. Chem. 271: 32635-32643, 1996. [PubMed: 8999038] [Full Text: https://doi.org/10.1074/jbc.271.51.32635]