Ormdl sphingolipid biosynthesis regulator 3

{{Short description|Protein-coding gene in the species Homo sapiens}}

ORMDL sphingolipid biosynthesis regulator 3 is a protein that in humans is encoded by the ORMDL3 gene.{{cite web | title = Entrez Gene: ORMDL sphingolipid biosynthesis regulator 3 | url = https://www.ncbi.nlm.nih.gov/gene/94103 }} Variants affecting the expression of this gene are associated with asthma in childhood.{{cite journal | vauthors = 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 | title = Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma | journal = Nature | volume = 448 | issue = 7152 | pages = 470–3 | date = July 2007 | pmid = 17611496 | doi = 10.1038/nature06014 | bibcode = 2007Natur.448..470M | hdl = 2027.42/62682 | s2cid = 4373589 | url = https://deepblue.lib.umich.edu/bitstream/2027.42/62682/1/nature06014.pdf | hdl-access = free }} 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.{{cite journal | vauthors = Miller M, Rosenthal P, Beppu A, Mueller JL, Hoffman HM, Tam AB, Doherty TA, McGeough MD, Pena CA, Suzukawa M, Niwa M, Broide DH | title = ORMDL3 transgenic mice have increased airway remodeling and airway responsiveness characteristic of asthma | journal = Journal of Immunology | volume = 192 | issue = 8 | pages = 3475–87 | date = April 2014 | pmid = 24623133 | pmc = 3981544 | doi = 10.4049/jimmunol.1303047 }}

Localisation

The ORMDL family, whose name stands for ORM1 (Saccharomyces cerevisiae)–like genes,{{cite journal | vauthors = Hjelmqvist L, Tuson M, Marfany G, Herrero E, Balcells S, Gonzàlez-Duarte R | title = ORMDL proteins are a conserved new family of endoplasmic reticulum membrane proteins | journal = Genome Biology | volume = 3 | issue = 6 | id= Art. No. RESEARCH0027 | date = 2002 | pages = RESEARCH0027 | pmid = 12093374 | pmc = 116724 | doi = 10.1186/gb-2002-3-6-research0027 | doi-access = free }} consists of three members (ORMDL1-3) which are localised in the membrane of the endoplasmic reticulum (ER).{{cite journal | vauthors = Davis D, Kannan M, Wattenberg B | title = Orm/ORMDL proteins: Gate guardians and master regulators | journal = Advances in Biological Regulation | volume = 70 | pages = 3–18 | date = December 2018 | pmid = 30193828 | pmc = 6251742 | doi = 10.1016/j.jbior.2018.08.002 | series = Sphingolipid Signaling in Chronic Disease }} 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),{{cite journal | vauthors = Breslow DK, Collins SR, Bodenmiller B, Aebersold R, Simons K, Shevchenko A, Ejsing CS, Weissman JS | title = Orm family proteins mediate sphingolipid homeostasis | journal = Nature | volume = 463 | issue = 7284 | pages = 1048–53 | date = February 2010 | pmid = 20182505 | pmc = 2877384 | doi = 10.1038/nature08787 | bibcode = 2010Natur.463.1048B }} but it may be present in relative excess of SPT physiologically, as ORMDL3 overexpression does not significantly reduce cellular sphingolipid biosynthesis.{{cite journal|year=2015|vauthors=Siow D, Sunkara M, Dunn TM, Morris AJ, Wattenberg B|title=ORMDL/serine palmitoyltransferase stoichiometry determines effects of ORMDL3 expression on sphingolipid biosynthesis|journal=Journal of Lipid Research|volume=56|issue=4|pages=898–908|doi=10.1194/jlr.M057539|pmid=25691431|pmc=4373746|doi-access=free}} ORMDL3 also has a role in regulating Ca²⁺ levels in the endoplasmic reticulum.{{cite journal|vauthors=Cantero-Recasens G, Fandos C, Rubio-Moscardo F, Valverde MA, Vicente R|title=The asthma-associated ORMDL3 gene product regulates endoplasmic reticulum-mediated calcium signaling and cellular stress|journal=Human Molecular Genetics|volume=19|issue=1|pages=111–121|doi=10.1093/hmg/ddp471|pmid=19819884|year=2010}} 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.{{cite journal | vauthors = Berridge MJ, Lipp P, Bootman MD | title = The versatility and universality of calcium signalling | journal = Nature Reviews. Molecular Cell Biology | volume = 1 | issue = 1 | pages = 11–21 | date = October 2000 | pmid = 11413485 | doi = 10.1038/35036035 | s2cid = 13150466 }} Dysregulation of Ca²⁺ has the key role in several pathological conditions like dysfunction of SERCA, asthma,{{cite journal | vauthors = 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 | title = Diminished sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) expression contributes to airway remodelling in bronchial asthma | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 106 | issue = 26 | pages = 10775–80 | date = June 2009 | pmid = 19541629 | pmc = 2699374 | doi = 10.1073/pnas.0902295106 | bibcode = 2009PNAS..10610775M | doi-access = free }} and Alzheimer's.{{cite journal | vauthors = Green KN, LaFerla FM | title = Linking calcium to Abeta and Alzheimer's disease | journal = Neuron | volume = 59 | issue = 2 | pages = 190–4 | date = July 2008 | pmid = 18667147 | doi = 10.1016/j.neuron.2008.07.013 | s2cid = 17020942 | doi-access = free }}

Clinical significance

Mutations in ORMDL3 are associated with inflammatory diseases like Crohn's disease, type 1 diabetes,{{cite journal | vauthors = 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 | title = Allele-specific chromatin remodeling in the ZPBP2/GSDMB/ORMDL3 locus associated with the risk of asthma and autoimmune disease | journal = American Journal of Human Genetics | volume = 85 | issue = 3 | pages = 377–93 | date = September 2009 | pmid = 19732864 | pmc = 2771592 | doi = 10.1016/j.ajhg.2009.08.007 }} and rheumatoid arthritis.{{cite journal | vauthors = 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 | title = Use of a multiethnic approach to identify rheumatoid- arthritis-susceptibility loci, 1p36 and 17q12 | journal = American Journal of Human Genetics | volume = 90 | issue = 3 | pages = 524–32 | date = March 2012 | pmid = 22365150 | pmc = 3309197 | doi = 10.1016/j.ajhg.2012.01.010 }}

Ormdl sphingolipid biosynthesis regulator 3

Localisation

Function

Clinical significance

References

Further reading