Ormdl sphingolipid biosynthesis regulator 3

Last updated
ORMDL3
Identifiers
Aliases ORMDL3 , ORMDL sphingolipid biosynthesis regulator 3
External IDs OMIM: 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

Contents

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 [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

ORMDL sphingolipid biosynthesis regulator 3 is a protein that in humans is encoded by the ORMDL3 gene. [5] Variants affecting the expression of this gene are 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]

Localisation

The ORMDL family, whose name stands for ORM1 (Saccharomyces cerevisiae)–like genes, [8] consists of three members (ORMDL1-3) which are localised in the membrane of the endoplasmic reticulum (ER). [9] All three human ORMDL genes encode 153 amino acid products. [9] The genes ORMDL1, ORMDL2 and ORMDL3 are located on human chromosomes 2q32, 12q13.2 and 17q21, respectively. [8]

Function

ORMDL3 negatively regulates de novo sphingolipid synthesis through interaction with serine palmitoyltransferase (SPT), [9] [10] but it may be present in relative excess of SPT physiologically, as ORMDL3 overexpression does not significantly reduce cellular sphingolipid biosynthesis. [11] ORMDL3 also has a role in regulating Ca2+ levels in the endoplasmic reticulum. [12] The ER is very important for generation, signaling function and storage 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 or SERCA) which return Ca2+ back to the ER. [13] Dysregulation of Ca2+ has the key role in several pathological conditions like dysfunction of SERCA, asthma, [14] and Alzheimer's. [15]

Clinical significance

Mutations in ORMDL3 are associated with inflammatory diseases like Crohn's disease, type 1 diabetes, [16] and rheumatoid arthritis. [17]

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References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000172057 - Ensembl, May 2017
  2. 1 2 3 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. 1 2 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. 1 2 3 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.

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