Ormdl sphingolipid biosynthesis regulator 3 explained

ORMDL sphingolipid biosynthesis regulator 3 is a protein that in humans is encoded by the ORMDL3 gene.^[1] Variants affecting the expression of this gene are associated with asthma in childhood.^[2] 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.^[3]

Localisation

The ORMDL family, whose name stands for ORM1 (Saccharomyces cerevisiae)–like genes,^[4] consists of three members (ORMDL1-3) which are localised in the membrane of the endoplasmic reticulum (ER).^[5] All three human ORMDL genes encode 153 amino acid products.^[5] The genes ORMDL1, ORMDL2 and ORMDL3 are located on human chromosomes 2q32, 12q13.2 and 17q21, respectively.^[4]

Function

ORMDL3 negatively regulates de novo sphingolipid synthesis through interaction with serine palmitoyltransferase (SPT),^[6] but it may be present in relative excess of SPT physiologically, as ORMDL3 overexpression does not significantly reduce cellular sphingolipid biosynthesis.^[7] ORMDL3 also has a role in regulating Ca²⁺ levels in the endoplasmic reticulum.^[8] 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.^[9] Dysregulation of Ca²⁺ has the key role in several pathological conditions like dysfunction of SERCA, asthma,^[10] and Alzheimer's.^[11]

Clinical significance

Mutations in ORMDL3 are associated with inflammatory diseases like Crohn's disease, type 1 diabetes,^[12] and rheumatoid arthritis.^[13]

Further reading

• Hirota T, Harada M, Sakashita M, Doi S, Miyatake A, Fujita K, Enomoto T, Ebisawa M, Yoshihara S, Noguchi E, Saito H, Nakamura Y, Tamari M . 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 . March 2008 . 18155279 . 10.1016/j.jaci.2007.09.038 . free .
• Galanter J, Choudhry S, Eng C, Nazario S, Rodríguez-Santana JR, Casal J, Torres-Palacios A, Salas J, Chapela R, Watson HG, Meade K, LeNoir M, Rodríguez-Cintrón W, Avila PC, Burchard EG . ORMDL3 gene is associated with asthma in three ethnically diverse populations . American Journal of Respiratory and Critical Care Medicine . 177 . 11 . 1194–200 . June 2008 . 18310477 . 2408437 . 10.1164/rccm.200711-1644OC .
• Tavendale R, Macgregor DF, Mukhopadhyay S, Palmer CN . 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 . April 2008 . 18395550 . 10.1016/j.jaci.2008.01.015 . free .
• Sleiman PM, Annaiah K, Imielinski M, Bradfield JP, Kim CE, Frackelton EC, Glessner JT, Eckert AW, Otieno FG, Santa E, Thomas K, Smith RM, Glaberson W, Garris M, Gunnlaugsson S, Chiavacci RM, Allen J, Spergel J, Grundmeier R, Grunstein MM, Magnusson M, Bisgaard H, Grant SF, Hakonarson H . ORMDL3 variants associated with asthma susceptibility in North Americans of European ancestry . The Journal of Allergy and Clinical Immunology . 122 . 6 . 1225–7 . December 2008 . 18760456 . 10.1016/j.jaci.2008.06.041 .

Notes and References

1. Web site: Entrez Gene: ORMDL sphingolipid biosynthesis regulator 3 .
2. Moffatt MF, Kabesch M, Liang L, Dixon AL, Strachan D, Heath S, Depner M, von Berg A, Bufe A, Rietschel E, Heinzmann A, Simma B, Frischer T, Willis-Owen SA, Wong KC, Illig T, Vogelberg C, Weiland SK, von Mutius E, Abecasis GR, Farrall M, Gut IG, Lathrop GM, Cookson WO . Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma . Nature . 448 . 7152 . 470–3 . July 2007 . 17611496 . 10.1038/nature06014 . 2007Natur.448..470M . 2027.42/62682 . 4373589 . free .
3. Miller M, Rosenthal P, Beppu A, Mueller JL, Hoffman HM, Tam AB, Doherty TA, McGeough MD, Pena CA, Suzukawa M, Niwa M, Broide DH . ORMDL3 transgenic mice have increased airway remodeling and airway responsiveness characteristic of asthma . Journal of Immunology . 192 . 8 . 3475–87 . April 2014 . 24623133 . 3981544 . 10.4049/jimmunol.1303047 .
4. Hjelmqvist L, Tuson M, Marfany G, Herrero E, Balcells S, Gonzàlez-Duarte R . ORMDL proteins are a conserved new family of endoplasmic reticulum membrane proteins . Genome Biology . 3 . 6 . Art. No. RESEARCH0027 . 2002 . RESEARCH0027 . 12093374 . 116724 . 10.1186/gb-2002-3-6-research0027 . free .
5. Davis D, Kannan M, Wattenberg B . Orm/ORMDL proteins: Gate guardians and master regulators . Advances in Biological Regulation . 70 . 3–18 . December 2018 . 30193828 . 6251742 . 10.1016/j.jbior.2018.08.002 . Sphingolipid Signaling in Chronic Disease .
6. Breslow DK, Collins SR, Bodenmiller B, Aebersold R, Simons K, Shevchenko A, Ejsing CS, Weissman JS . Orm family proteins mediate sphingolipid homeostasis . Nature . 463 . 7284 . 1048–53 . February 2010 . 20182505 . 2877384 . 10.1038/nature08787 . 2010Natur.463.1048B .
7. 2015. Siow D, Sunkara M, Dunn TM, Morris AJ, Wattenberg B. ORMDL/serine palmitoyltransferase stoichiometry determines effects of ORMDL3 expression on sphingolipid biosynthesis. Journal of Lipid Research. 56. 4. 898–908. 10.1194/jlr.M057539. 25691431. 4373746. free.
8. Cantero-Recasens G, Fandos C, Rubio-Moscardo F, Valverde MA, Vicente R. The asthma-associated ORMDL3 gene product regulates endoplasmic reticulum-mediated calcium signaling and cellular stress. Human Molecular Genetics. 19. 1. 111–121. 10.1093/hmg/ddp471. 19819884. 2010.
9. Berridge MJ, Lipp P, Bootman MD . The versatility and universality of calcium signalling . Nature Reviews. Molecular Cell Biology . 1 . 1 . 11–21 . October 2000 . 11413485 . 10.1038/35036035 . 13150466 .
10. Mahn K, Hirst SJ, Ying S, Holt MR, Lavender P, Ojo OO, Siew L, Simcock DE, McVicker CG, Kanabar V, Snetkov VA, O'Connor BJ, Karner C, Cousins DJ, Macedo P, Chung KF, Corrigan CJ, Ward JP, Lee TH . 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 . June 2009 . 19541629 . 2699374 . 10.1073/pnas.0902295106 . 2009PNAS..10610775M . free .
11. Green KN, LaFerla FM . Linking calcium to Abeta and Alzheimer's disease . Neuron . 59 . 2 . 190–4 . July 2008 . 18667147 . 10.1016/j.neuron.2008.07.013 . 17020942 . free .
12. Verlaan DJ, Berlivet S, Hunninghake GM, Madore AM, Larivière M, Moussette S, Grundberg E, Kwan T, Ouimet M, Ge B, Hoberman R, Swiatek M, Dias J, Lam KC, Koka V, Harmsen E, Soto-Quiros M, Avila L, Celedón JC, Weiss ST, Dewar K, Sinnett D, Laprise C, Raby BA, Pastinen T, Naumova AK . 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 . September 2009 . 19732864 . 2771592 . 10.1016/j.ajhg.2009.08.007 .
13. Kurreeman FA, Stahl EA, Okada Y, Liao K, Diogo D, Raychaudhuri S, Freudenberg J, Kochi Y, Patsopoulos NA, Gupta N, Sandor C, Bang SY, Lee HS, Padyukov L, Suzuki A, Siminovitch K, Worthington J, Gregersen PK, Hughes LB, Reynolds RJ, Bridges SL, Bae SC, Yamamoto K, Plenge RM . Use of a multiethnic approach to identify rheumatoid- arthritis-susceptibility loci, 1p36 and 17q12 . American Journal of Human Genetics . 90 . 3 . 524–32 . March 2012 . 22365150 . 3309197 . 10.1016/j.ajhg.2012.01.010 .