MFSD2
{{Short description|Protein-coding gene in the species Homo sapiens}}
{{Use dmy dates|date=April 2016}}
{{Infobox_gene}}
Major facilitator superfamily domain-containing protein 2 (MFSD2 or MFSD2A) -- also known as sodium-dependent lysophosphatidylcholine symporter 1 -- is a protein that in humans is encoded by the MFSD2A gene.{{cite web|title=Sodium-dependent lysophosphatidylcholine symporter 1|url=https://www.uniprot.org/uniprot/Q8NA29|website=UniProt|access-date=2 April 2016}} MFSD2A is a membrane transport protein that is expressed in the endothelium of the blood–brain barrier (BBB) and has an essential role in BBB formation and function. Genetic ablation of MFSD2A results in leaky BBB and increases central nervous system endothelial cell vesicular transcytosis without otherwise affecting tight junctions.{{cite journal |vauthors=Ben-Zvi A, Lacoste B, Kur E, Andreone BJ, Mayshar Y, Yan H, Gu C | title = Mfsd2a is critical for the formation and function of the blood-brain barrier | journal = Nature | volume = 509| issue = 7501| pages = 507–11|date=May 2014 | pmid = 24828040 | doi = 10.1038/nature13324 |pmc=4134871| bibcode = 2014Natur.509..507B }}
- {{cite web |author=Stephanie Dutchen |date=May 14, 2014 |title=Breaking Through the Barrier |website=Harvard Medical School |url=http://hms.harvard.edu/news/breaking-through-barrier-5-14-14 |archive-url=https://web.archive.org/web/20140515174650/http://hms.harvard.edu/news/breaking-through-barrier-5-14-14 |archive-date=2014-05-15}} MFSD2A is an atypical SLC,{{Cite journal|last1=Perland|first1=Emelie|last2=Fredriksson|first2=Robert|date=March 2017|title=Classification Systems of Secondary Active Transporters|journal=Trends in Pharmacological Sciences|volume=38|issue=3|pages=305–315|doi=10.1016/j.tips.2016.11.008|issn=1873-3735|pmid=27939446}} thus a predicted SLC transporter.{{Cite journal|last1=Perland|first1=Emelie|last2=Bagchi|first2=Sonchita|last3=Klaesson|first3=Axel|last4=Fredriksson|first4=Robert|date=September 2017|title=Characteristics of 29 novel atypical solute carriers of major facilitator superfamily type: evolutionary conservation, predicted structure and neuronal co-expression|journal=Open Biology|volume=7|issue=9|doi=10.1098/rsob.170142|issn=2046-2441|pmid=28878041|pmc=5627054|page=170142}} It clusters phylogenetically to AMTF8.
In addition to transport of other lysophosphatidylcholines across the BBB, MSFD2A is the primary mechanism for docosahexaenoic acid (DHA, an omega-3 fatty acid) uptake and transport into the brain. It may also be responsible for uptake and transport of tunicamycin.{{cite journal |vauthors=Angers M, Uldry M, Kong D, Gimble JM, Jetten AM | title = Mfsd2a encodes a novel major facilitator superfamily domain-containing protein highly induced in brown adipose tissue during fasting and adaptive thermogenesis | journal = Biochem J | volume = 416 | issue = 3 | pages = 347–55 | date = November 2008 | pmid = 18694395 | pmc = 2587516 | doi = 10.1042/BJ20080165 }}{{cite web | title = Entrez Gene: MFSD2 major facilitator superfamily domain containing 2| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=84879}}{{cite journal |vauthors=Reiling JH, Clish CB, Carette JE, Varadarajan M, Brummelkamp TR, Sabatini DM | title = A haploid genetic screen identifies the major facilitator domain containing 2A (MFSD2A) transporter as a key mediator in the response to tunicamycin | journal = Proc Natl Acad Sci U S A | volume = 108 | issue = 29 | pages = 11756–65 | date = July 2011 | pmid = 21677192 | pmc = 3141996 | doi = 10.1073/pnas.1018098108 | bibcode = 2011PNAS..10811756R | doi-access = free }}
Complete loss of MFSD2A in human leads to a recessive lethal microcephaly syndrome consisting of enlarged lateral ventricles and underdevelopment of the cerebellum and brainstem. This is presumably due to loss of uptake of essential polyunsaturated fatty acids by the brain endothelial cells, which utilize MFSD2A as a transporter for these fats. Serum from patients showed elevated levels of essential polyunsaturated fatty acids, presumably due to the inability of vascular cells to uptake these lipids in the absence of protein function. Without the ability to uptake these fats into endothelial cells, there is breakdown of the blood-brain-barrier and loss of brain volume. This was demonstrated in a zebrafish model by intracardiac injection of dye, which was found to extravasate into the brain parenchyma following inactivating one of the paralogues of MSFD2A known as mfsd2aa.Nat Genet. 2015 Jul;47(7):809-13
References
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Further reading
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- {{cite journal |vauthors=Clark HF, Gurney AL, Abaya E, Baker K, Baldwin D, Brush J, Chen J, Chow B, Chui C, Crowley C, Currell B, Deuel B, Dowd P, Eaton D, Foster J, Grimaldi C, Gu Q, Hass PE, Heldens S, Huang A, Kim HS, Klimowski L, Jin Y, Johnson S, Lee J, Lewis L, Liao D, Mark M, Robbie E, Sanchez C, Schoenfeld J, Seshagiri S, Simmons L, Singh J, Smith V, Stinson J, Vagts A, Vandlen R, Watanabe C, Wieand D, Woods K, Xie MH, Yansura D, Yi S, Yu G, Yuan J, Zhang M, Zhang Z, Goddard A, Wood WI, Godowski P, Gray A | title = The Secreted Protein Discovery Initiative (SPDI), a Large-Scale Effort to Identify Novel Human Secreted and Transmembrane Proteins: A Bioinformatics Assessment | journal = Genome Res. | volume = 13 | issue = 10 | pages = 2265–70 | year = 2003 | pmid = 12975309 | pmc = 403697 | doi = 10.1101/gr.1293003 }}
- {{cite journal |vauthors=Yamada S, Ohira M, Horie H, Ando K, Takayasu H, Suzuki Y, Sugano S, Hirata T, Goto T, Matsunaga T, Hiyama E, Hayashi Y, Ando H, Suita S, Kaneko M, Sasaki F, Hashizume K, Ohnuma N, Nakagawara A | title = Expression profiling and differential screening between hepatoblastomas and the corresponding normal livers: identification of high expression of the PLK1 oncogene as a poor-prognostic indicator of hepatoblastomas | journal = Oncogene | volume = 23 | issue = 35 | pages = 5901–11 | year = 2004 | pmid = 15221005 | doi = 10.1038/sj.onc.1207782 | doi-access = free }}
- {{cite journal |vauthors=Wan D, Gong Y, Qin W, Zhang P, Li J, Wei L, Zhou X, Li H, Qiu X, Zhong F, He L, Yu J, Yao G, Jiang H, Qian L, Yu Y, Shu H, Chen X, Xu H, Guo M, Pan Z, Chen Y, Ge C, Yang S, Gu J | title = Large-scale cDNA transfection screening for genes related to cancer development and progression | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 101 | issue = 44 | pages = 15724–9 | year = 2004 | pmid = 15498874 | pmc = 524842 | doi = 10.1073/pnas.0404089101 | bibcode = 2004PNAS..10115724W | doi-access = free }}
- {{cite journal |vauthors=Spinola M, Falvella FS, Galvan A, Pignatiello C, Leoni VP, Pastorino U, Paroni R, Chen S, Skaug V, Haugen A, Dragani TA | title = Ethnic differences in frequencies of gene polymorphisms in the MYCL1 region and modulation of lung cancer patients' survival | journal = Lung Cancer | volume = 55 | issue = 3 | pages = 271–7 | year = 2007 | pmid = 17145094 | doi = 10.1016/j.lungcan.2006.10.023 | hdl = 2434/25016 | url = https://air.unimi.it/bitstream/2434/25016/2/93-Ethnic%20differences%20in%20frequencies%20of%20gene%20Lung%20cancer.pdf | hdl-access = free }}
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