Ormdl sphingolipid biosynthesis regulator 3

ORMDL sphingolipid biosynthesis regulator 3 is a protein that in humans is encoded by the ORMDL3 gene.[5] This gene is associated with asthma in childhood.[6] 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.[7]

ORMDL3
Identifiers
AliasesORMDL3, ORMDL sphingolipid biosynthesis regulator 3
External IDsOMIM: 610075 MGI: 1913862 HomoloGene: 57032 GeneCards: ORMDL3
Orthologs
SpeciesHumanMouse
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 MbChr 11: 98.47 – 98.48 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Localisation

Mouse and human ORMDL3 gene encode 153 aa. ORMDL family consists of three members (ORMDL1-3) which are localised in the membrane of endoplasmic reticulum (ER).[8] Human ORMDL1, ORMDL2 and ORMDL3 are localised in chromosomes 2q32, 12q13.2 a 17q21.[9]

Function

ORMDL3 plays role in sphingolipid synthesis like negative regulators.[8][10] It also has a role in regulation of Ca2+ levels in the endoplasmic reticulum. ER is very important for generation, signalisation, functioning and store of intracellular Ca2+. There are channels, which control the exit of Ca2+ from the ER into the cytoplasm and also pumps (sarco-endoplasmic reticulum Ca2+ ATPase (SERCA)) which return Ca2+ back to the ER.[11] Dysregulation of Ca2+ has the key role in several pathological conditions like dysfunction of SERCA, asthma,[12] and Alzheimer's.[13]

Clinical significance

Mutations in ORMDL3 are associated with inflammatory disease like Crohn's disease, type 1 diabetes,[14] and rheumatoid arthritis.[15]

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. 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.
  9. 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.
  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. 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.
  12. 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.
  13. 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.
  14. 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.
  15. 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
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