MFSD2

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.^[5] 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.^[5] Genetic ablation of MFSD2A results in leaky BBB and increases central nervous system endothelial cell vesicular transcytosis without otherwise affecting tight junctions.^[6] MFSD2A is an atypical SLC,^[7] thus a predicted SLC transporter.^[8] It clusters phylogenetically to AMTF8.^[8]

MFSD2A
Identifiers
Aliases	MFSD2A, MFSD2, NLS1, MCPH15, major facilitator superfamily domain containing 2A, NEDMISBA, SLC59A1
External IDs	OMIM: 614397; MGI: 1923824; HomoloGene: 19229; GeneCards: MFSD2A; OMA:MFSD2A - orthologs
Gene location (Human) Chr. Chromosome 1 (human)[1] Band 1p34.2 Start 39,955,112 bp[1] End 39,969,968 bp[1]
Gene location (Mouse) Chr. Chromosome 4 (mouse)[2] Band 4|4 D2.2 Start 122,840,643 bp[2] End 122,854,981 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in right lobe of liver skin of abdomen mucosa of ileum skin of leg seminal vesicula skin of arm corpus epididymis right testis left testis upper lobe of left lung Top expressed in primary oocyte zygote otolith organ utricle right kidney epithelium of lens sciatic nerve superior frontal gyrus secondary oocyte visual cortex More reference expression data BioGPS n/a
Gene ontology Molecular function symporter activity phospholipid transporter activity fatty acid transmembrane transporter activity lysophospholipid:sodium symporter activity transporter activity Cellular component integral component of membrane integral component of plasma membrane endoplasmic reticulum membrane endoplasmic reticulum membrane plasma membrane Biological process lipid transport fatty acid transport transcytosis lipid transport across blood-brain barrier transmembrane transport establishment of blood-brain barrier phosphatidylcholine biosynthetic process hippocampus development lysophospholipid transport carbohydrate transport organic substance transport Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 84879 76574 Ensembl ENSG00000168389 ENSMUSG00000028655 UniProt Q8NA29 Q5SSK0 Q9DA75 RefSeq (mRNA) NM_001136493 NM_001287808 NM_001287809 NM_032793 NM_001349821 NM_001349822 NM_001349823 NM_029662 RefSeq (protein) NP_001129965 NP_001274737 NP_001274738 NP_116182 NP_001336750 NP_001336751 NP_001336752 NP_083938 Location (UCSC) Chr 1: 39.96 – 39.97 Mb Chr 4: 122.84 – 122.85 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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.^[5] It may also be responsible for uptake and transport of tunicamycin.^[9][10][11]

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.^[12]

References

1. GRCh38: Ensembl release 89: ENSG00000168389 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000028655 – 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. "Sodium-dependent lysophosphatidylcholine symporter 1". UniProt. Retrieved 2 April 2016.
6. Ben-Zvi A, Lacoste B, Kur E, Andreone BJ, Mayshar Y, Yan H, Gu C (May 2014). "Mfsd2a is critical for the formation and function of the blood-brain barrier". Nature. 509 (7501): 507–11. Bibcode:2014Natur.509..507B. doi:10.1038/nature13324. PMC 4134871. PMID 24828040.

   • Stephanie Dutchen (14 May 2014). "Breaking Through the Barrier". Harvard Medical School. Archived from the original on 15 May 2014.
7. Perland, Emelie; Fredriksson, Robert (March 2017). "Classification Systems of Secondary Active Transporters". Trends in Pharmacological Sciences. 38 (3): 305–315. doi:10.1016/j.tips.2016.11.008. ISSN 1873-3735. PMID 27939446.
8. Perland, Emelie; Bagchi, Sonchita; Klaesson, Axel; Fredriksson, Robert (September 2017). "Characteristics of 29 novel atypical solute carriers of major facilitator superfamily type: evolutionary conservation, predicted structure and neuronal co-expression". Open Biology. 7 (9): 170142. doi:10.1098/rsob.170142. ISSN 2046-2441. PMC 5627054. PMID 28878041.
9. Angers M, Uldry M, Kong D, Gimble JM, Jetten AM (November 2008). "Mfsd2a encodes a novel major facilitator superfamily domain-containing protein highly induced in brown adipose tissue during fasting and adaptive thermogenesis". Biochem J. 416 (3): 347–55. doi:10.1042/BJ20080165. PMC 2587516. PMID 18694395.
10. "Entrez Gene: MFSD2 major facilitator superfamily domain containing 2".
11. Reiling JH, Clish CB, Carette JE, Varadarajan M, Brummelkamp TR, Sabatini DM (July 2011). "A haploid genetic screen identifies the major facilitator domain containing 2A (MFSD2A) transporter as a key mediator in the response to tunicamycin". Proc Natl Acad Sci U S A. 108 (29): 11756–65. Bibcode:2011PNAS..10811756R. doi:10.1073/pnas.1018098108. PMC 3141996. PMID 21677192.
12. Nat Genet. 2015 Jul;47(7):809-13

Further reading

• 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 (2003). "The Secreted Protein Discovery Initiative (SPDI), a Large-Scale Effort to Identify Novel Human Secreted and Transmembrane Proteins: A Bioinformatics Assessment". Genome Res. 13 (10): 2265–70. doi:10.1101/gr.1293003. PMC 403697. PMID 12975309.
• 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 (2004). "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". Oncogene. 23 (35): 5901–11. doi:10.1038/sj.onc.1207782. PMID 15221005.
• 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 (2004). "Large-scale cDNA transfection screening for genes related to cancer development and progression". Proc. Natl. Acad. Sci. U.S.A. 101 (44): 15724–9. Bibcode:2004PNAS..10115724W. doi:10.1073/pnas.0404089101. PMC 524842. PMID 15498874.
• Spinola M, Falvella FS, Galvan A, Pignatiello C, Leoni VP, Pastorino U, Paroni R, Chen S, Skaug V, Haugen A, Dragani TA (2007). "Ethnic differences in frequencies of gene polymorphisms in the MYCL1 region and modulation of lung cancer patients' survival" (PDF). Lung Cancer. 55 (3): 271–7. doi:10.1016/j.lungcan.2006.10.023. hdl:2434/25016. PMID 17145094.