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
External IDs	OMIM: 614397 MGI: 1923824 HomoloGene: 19229 GeneCards: MFSD2A
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 122,946,850 bp[2] End 122,961,188 bp[2]
Gene ontology Molecular function • symporter activity • phospholipid transporter activity • GO:0015246 fatty acid transmembrane transporter activity • lysophospholipid transporter activity • transporter activity Cellular component • integral component of membrane • integral component of plasma membrane • endoplasmic reticulum membrane • endoplasmic reticulum • membrane • cell 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: 122.95 – 122.96 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. doi:10.1038/nature13324. PMC 4134871. PMID 24828040. Lay summary – Harvard Medical School.
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. 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. 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. PMID 17145094.