HGNC Approved Gene Symbol: ORMDL3
Cytogenetic location: 17q21.1 Genomic coordinates (GRCh38) : 17:39,921,041-39,927,601 (from NCBI)
By searching databases for sequences similar to ORMDL1 (610073), Hjelmqvist et al. (2002) identified ORMDL3. The deduced 153-amino acid protein contains 4 putative transmembrane domains and shares 84%, 80%, and 96% amino acid identity with ORMDL1, ORMDL2 (610074), and mouse Ormdl3, respectively. It also shares significant homology with its yeast orthologs, Orm1 and Orm2. RT-PCR detected ORMDL3 expression in all adult and fetal tissues examined. Fluorescence-tagged ORMDL3 localized with an endoplasmic reticulum marker following transfection into COS-7 cells. McGovern et al. (2010) confirmed that ORMDL3 localizes to the endoplasmic reticulum.
Hjelmqvist et al. (2002) determined that the ORMDL3 gene contains 3 coding exons and spans at least 2 kb.
By genomic sequence analysis, Hjelmqvist et al. (2002) mapped the ORMDL3 gene to chromosome 17q21.1.
Starting from an unbiased functional genomic approach in S. cerevisiae, Breslow et al. (2010) identified ORM proteins, including ORMDL3, as negative regulators of sphingolipid synthesis that form a conserved complex with serine palmitoyltransferase (605712), the first and rate-limiting enzyme in sphingolipid production. Breslow et al. (2010) also defined a regulatory pathway in which phosphorylation of ORM proteins relieves their inhibitory activity when sphingolipid production is disrupted. Changes in ORM gene expression or mutations to their phosphorylation sites cause dysregulation of sphingolipid metabolism. Breslow et al. (2010) concluded that their work identified the ORM proteins as critical mediators of sphingolipid homeostasis and raised the possibility that sphingolipid misregulation contributes to the development of childhood asthma.
Cantero-Recasens et al. (2010) determined that ORMDL3 altered endoplasmic reticulum (ER)-mediated calcium homeostasis and facilitated the unfolded-protein response (UPR). Heterologous expression of human ER-resident transmembrane ORMDL3 protein increased resting cytosolic calcium levels and reduced ER-mediated calcium signaling, an effect reversed by coexpression with the sarcoendoplasmic reticulum calcium pump, SERCA (ATP2A1; 108730). Increased ORMDL3 expression also promoted stronger activation of UPR-transducing molecules and target genes, while siRNA-mediated knockdown of endogenous ORMDL3 potentiated ER calcium release and attenuated the UPR. Cantero-Recasens et al. (2010) concluded that ORMDL3 binds and inhibits SERCA resulting in a reduced ER calcium concentration and increased unfolded-protein response.
In studies in epithelial cells, McGovern et al. (2010) found that overexpression of ORMDL3 decreased both the basal and endoplasmic reticulum (ER)-stress-induced UPR. Knockdown of ORMDL3 expression induced a higher UPR after tunicamycin or thapsigargin stimulation, indicating that ORMDL3 expression levels can regulate UPR and that ORMDL3 might be an important factor in ensuring ER homeostasis.
For discussion of an association between variation in the ORMDL3 gene and inflammatory bowel disease, see IBD22 (612380).
Moffatt et al. (2007) characterized more than 317,000 SNPs in DNA from 994 patients with childhood onset asthma and 1,243 nonasthmatics, using family and case-referent panels. The authors showed multiple markers on chromosome 17q21 (ASRT6; 611403) to be strongly and reproducibly associated with childhood onset asthma in family and case-referent panels with a combined p value of less than 10(-12). Moffatt et al. (2007) systematically evaluated the relationship between markers of the 17q21 locus and transcript levels of genes in Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines from children in the asthma family family used in their association study. The SNPs associated with childhood asthma were consistently and strongly associated (p less than 10(22)) in cis with transcript levels of ORMDL3, a member of a gene family that encodes transmembrane proteins anchored in the endoplasmic reticulum. Moffatt et al. (2007) concluded that genetic variants regulating ORMDL3 expression are determinants of susceptibility to childhood asthma.
Breslow, D. K., Collins, S. R., Bodenmiller, B., Aebersold, R., Simons, K., Shevchenko, A., Ejsing, C. S., Weissman, J. S. Orm family proteins mediate sphingolipid homeostasis. Nature 463: 1048-1053, 2010. [PubMed: 20182505] [Full Text: https://doi.org/10.1038/nature08787]
Cantero-Recasens, G., Fandos, C., Rubio-Moscardo, F., Valverde, M. A., Vicente, R. The asthma-associated ORMDL3 gene product regulates endoplasmic reticulum-mediated calcium signaling and cellular stress. Hum. Molec. Genet. 19: 111-121, 2010. [PubMed: 19819884] [Full Text: https://doi.org/10.1093/hmg/ddp471]
Hjelmqvist, L., Tuson, M., Marfany, G., Herrero, E., Balcells, S., Gonzalez-Duarte, R. ORMDL proteins are a conserved new family of endoplasmic reticulum membrane proteins. Genome Biol. 3: RESEARCH0027, 2002. [PubMed: 12093374] [Full Text: https://doi.org/10.1186/gb-2002-3-6-research0027]
McGovern, D. P. B., Gardet, A., Torkvist, L., Goyette, P., Essers, J., Taylor, K. D., Neale, B. M., Ong, R. T. H., Lagace, C., Li, C., Green, T., Stevens, C. R., and 43 others. Genome-wide association identifies multiple ulcerative colitis susceptibility loci. Nature Genet. 42: 332-337, 2010. Note: Erratum: Nature Genet. 43: 388 only, 2011. [PubMed: 20228799] [Full Text: https://doi.org/10.1038/ng.549]
Moffatt, M. F., Kabesch, M., Liang, L., Dixon, A. L., Strachan, D., Heath, S., Depner, M., von Berg, A., Bufe, A., Rietschel, E., Heinzmann, A., Simma, B., and 12 others. Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma. Nature 448: 470-473, 2007. [PubMed: 17611496] [Full Text: https://doi.org/10.1038/nature06014]