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ORMDL3
Identifiers
Aliases	ORMDL3, ORMDL sphingolipid biosynthesis regulator 3
External IDs	OMIM: 610075; MGI: 1913862; HomoloGene: 57032; GeneCards: ORMDL3; OMA:ORMDL3 - orthologs
Gene location (Human) Chr. Chromosome 17 (human) Band 17q21.1 Start 39,921,041 bp End 39,927,601 bp
Gene location (Mouse) Chr. Chromosome 11 (mouse) Band 11|11 D Start 98,472,082 bp End 98,478,194 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in right lobe of liver bone marrow cells granulocyte stromal cell of endometrium body of pancreas epithelium of colon anterior pituitary olfactory zone of nasal mucosa abdominal fat apex of heart Top expressed in olfactory epithelium brown adipose tissue saccule white adipose tissue lactiferous gland lip epithelium of small intestine choroid plexus of fourth ventricle tunica adventitia of aorta neural layer of retina More reference expression data BioGPS n/a
Gene ontology Molecular function protein binding Cellular component integral component of membrane SPOTS complex endoplasmic reticulum membrane endoplasmic reticulum membrane plasma membrane secretory granule membrane specific granule membrane Biological process ceramide metabolic process cellular sphingolipid homeostasis neutrophil degranulation negative regulation of ceramide biosynthetic process Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 94103 66612 Ensembl ENSG00000172057 ENSMUSG00000038150 UniProt Q8N138 Q9CPZ6 RefSeq (mRNA) NM_139280 NM_001320801 NM_001320802 NM_001320803 NM_016471 NM_025661 RefSeq (protein) NP_001307730 NP_001307731 NP_001307732 NP_644809 NP_079937 Location (UCSC) Chr 17: 39.92 – 39.93 Mb Chr 11: 98.47 – 98.48 Mb PubMed search
Wikidata
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ORMDL sphingolipid biosynthesis regulator 3 is a protein that in humans is encoded by the ORMDL3 gene. Variants affecting the expression of this gene are associated with asthma in childhood. Transgenic mice which overexpress human ORMDL3 have increased levels of IgE. This correlated with increased numbers of macrophages, neutrophils, eosinophils, CD4 and enhanced Th2 cytokine levels in the lung tissue.

Localisation

The ORMDL family, whose name stands for ORM1 (Saccharomyces cerevisiae)–like genes, consists of three members (ORMDL1-3) which are localised in the membrane of the endoplasmic reticulum (ER). All three human ORMDL genes encode 153 amino acid products. The genes ORMDL1, ORMDL2 and ORMDL3 are located on human chromosomes 2q32, 12q13.2 and 17q21, respectively.

Function

ORMDL3 negatively regulates de novo sphingolipid synthesis through interaction with serine palmitoyltransferase (SPT), but it may be present in relative excess of SPT physiologically, as ORMDL3 overexpression does not significantly reduce cellular sphingolipid biosynthesis. ORMDL3 also has a role in regulating Ca levels in the endoplasmic reticulum. The ER is very important for generation, signaling function and storage of intracellular Ca. There are channels, which control the exit of Ca from the ER into the cytoplasm and also pumps (sarco-endoplasmic reticulum Ca ATPase or SERCA) which return Ca back to the ER. Dysregulation of Ca has the key role in several pathological conditions like dysfunction of SERCA, asthma, and Alzheimer's.

Clinical significance

Mutations in ORMDL3 are associated with inflammatory diseases like Crohn's disease, type 1 diabetes, and rheumatoid arthritis.

References

1. ^ GRCh38: Ensembl release 89: ENSG00000172057 – Ensembl, May 2017
2. ^ GRCm38: Ensembl release 89: ENSMUSG00000038150 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. "Entrez Gene: ORMDL sphingolipid biosynthesis regulator 3".
6. Moffatt MF, Kabesch M, Liang L, Dixon AL, Strachan D, Heath S, et al. (July 2007). "Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma" (PDF). Nature. 448 (7152): 470–3. Bibcode:2007Natur.448..470M. doi:10.1038/nature06014. hdl:2027.42/62682. PMID 17611496. S2CID 4373589.
7. Miller M, Rosenthal P, Beppu A, Mueller JL, Hoffman HM, Tam AB, et al. (April 2014). "ORMDL3 transgenic mice have increased airway remodeling and airway responsiveness characteristic of asthma". Journal of Immunology. 192 (8): 3475–87. doi:10.4049/jimmunol.1303047. PMC 3981544. PMID 24623133.
8. ^ Hjelmqvist L, Tuson M, Marfany G, Herrero E, Balcells S, Gonzàlez-Duarte R (2002). "ORMDL proteins are a conserved new family of endoplasmic reticulum membrane proteins". Genome Biology. 3 (6): RESEARCH0027. doi:10.1186/gb-2002-3-6-research0027. PMC 116724. PMID 12093374. Art. No. RESEARCH0027.
9. ^ Davis D, Kannan M, Wattenberg B (December 2018). "Orm/ORMDL proteins: Gate guardians and master regulators". Advances in Biological Regulation. Sphingolipid Signaling in Chronic Disease. 70: 3–18. doi:10.1016/j.jbior.2018.08.002. PMC 6251742. PMID 30193828.
10. Breslow DK, Collins SR, Bodenmiller B, Aebersold R, Simons K, Shevchenko A, et al. (February 2010). "Orm family proteins mediate sphingolipid homeostasis". Nature. 463 (7284): 1048–53. Bibcode:2010Natur.463.1048B. doi:10.1038/nature08787. PMC 2877384. PMID 20182505.
11. Siow D, Sunkara M, Dunn TM, Morris AJ, Wattenberg B (2015). "ORMDL/serine palmitoyltransferase stoichiometry determines effects of ORMDL3 expression on sphingolipid biosynthesis". Journal of Lipid Research. 56 (4): 898–908. doi:10.1194/jlr.M057539. PMC 4373746. PMID 25691431.
12. Cantero-Recasens G, Fandos C, Rubio-Moscardo F, Valverde MA, Vicente R (2010). "The asthma-associated ORMDL3 gene product regulates endoplasmic reticulum-mediated calcium signaling and cellular stress". Human Molecular Genetics. 19 (1): 111–121. doi:10.1093/hmg/ddp471. PMID 19819884.
13. Berridge MJ, Lipp P, Bootman MD (October 2000). "The versatility and universality of calcium signalling". Nature Reviews. Molecular Cell Biology. 1 (1): 11–21. doi:10.1038/35036035. PMID 11413485. S2CID 13150466.
14. Mahn K, Hirst SJ, Ying S, Holt MR, Lavender P, Ojo OO, et al. (June 2009). "Diminished sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) expression contributes to airway remodelling in bronchial asthma". Proceedings of the National Academy of Sciences of the United States of America. 106 (26): 10775–80. Bibcode:2009PNAS..10610775M. doi:10.1073/pnas.0902295106. PMC 2699374. PMID 19541629.
15. Green KN, LaFerla FM (July 2008). "Linking calcium to Abeta and Alzheimer's disease". Neuron. 59 (2): 190–4. doi:10.1016/j.neuron.2008.07.013. PMID 18667147. S2CID 17020942.
16. Verlaan DJ, Berlivet S, Hunninghake GM, Madore AM, Larivière M, Moussette S, et al. (September 2009). "Allele-specific chromatin remodeling in the ZPBP2/GSDMB/ORMDL3 locus associated with the risk of asthma and autoimmune disease". American Journal of Human Genetics. 85 (3): 377–93. doi:10.1016/j.ajhg.2009.08.007. PMC 2771592. PMID 19732864.
17. Kurreeman FA, Stahl EA, Okada Y, Liao K, Diogo D, Raychaudhuri S, et al. (March 2012). "Use of a multiethnic approach to identify rheumatoid- arthritis-susceptibility loci, 1p36 and 17q12". American Journal of Human Genetics. 90 (3): 524–32. doi:10.1016/j.ajhg.2012.01.010. PMC 3309197. PMID 22365150.

Further reading

• Hirota T, Harada M, Sakashita M, Doi S, Miyatake A, Fujita K, et al. (March 2008). "Genetic polymorphism regulating ORM1-like 3 (Saccharomyces cerevisiae) expression is associated with childhood atopic asthma in a Japanese population". The Journal of Allergy and Clinical Immunology. 121 (3): 769–70. doi:10.1016/j.jaci.2007.09.038. PMID 18155279.
• Galanter J, Choudhry S, Eng C, Nazario S, Rodríguez-Santana JR, Casal J, et al. (June 2008). "ORMDL3 gene is associated with asthma in three ethnically diverse populations". American Journal of Respiratory and Critical Care Medicine. 177 (11): 1194–200. doi:10.1164/rccm.200711-1644OC. PMC 2408437. PMID 18310477.
• Tavendale R, Macgregor DF, Mukhopadhyay S, Palmer CN (April 2008). "A polymorphism controlling ORMDL3 expression is associated with asthma that is poorly controlled by current medications". The Journal of Allergy and Clinical Immunology. 121 (4): 860–3. doi:10.1016/j.jaci.2008.01.015. PMID 18395550.
• Sleiman PM, Annaiah K, Imielinski M, Bradfield JP, Kim CE, Frackelton EC, et al. (December 2008). "ORMDL3 variants associated with asthma susceptibility in North Americans of European ancestry". The Journal of Allergy and Clinical Immunology. 122 (6): 1225–7. doi:10.1016/j.jaci.2008.06.041. PMID 18760456.

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