Major facilitator superfamily domain-containing protein 2 is a protein that in humans is encoded by the MFSD2A gene. It is a transmembrane protein which may be responsible for uptake and transport of tunicamycin at the plasma membrane. Mfsd2a is expressed in blood vessels that form the blood–brain barrier (BBB). Knockout of Mfsd2a increases results in leaky BBB and in particular transcytosis without otherwise affecting tight-junctions.
CHEMICAL STRUCTURE AND IMAGES
In terms of sequence and structural similarities, MFSD2A is similar to genes for bacterial permeases and symporter proteins, which belong to a protein superfamily of 10–12 transmembrane domains, and it is presumed to be a carbohydrate transporter. The gene MFSD2A is 14.84 kb in length and consists of 14 exons and spans about 7.7 kb. MFSD2a and its additional closely related protein, Mfsd2b have most intron/exon junctions conserved between the two genes, suggesting that they are derived from a common ancestor. Mfsd2a and Mfsd2b share a 12 transmembrane alpha-helical domain structure that bears greatest similarity to that of the bacterial Na(+)/melibiose symporters. Confocal microscopy demonstrated that Mfsd2a localizes to the endoplasmic reticulum.
Protein Aminoacids Percentage
According to the NCBI SNP database (http://www.ncbi.nlm.nih.gov/snp, 26 January 2013, date last accessed), there are many potential functional SNPs [e.g. non-synonymous SNPs promoter SNPs and SNPs located in 3′ and 5′ untranslated region] identified in other ethnic populations within the region from 20 kb upstream of TRIT1 to 20 kb downstream of MFSD2A. An increasing number of studies have revealed that genetic variants in the TRIT1, MYCL1 and MFSD2A region may affect some particular types of cancer, including gastric cancer (21–25). However, most studies have only focused on a few individual SNPs, such as rs3134613 and rs3738671.
Gene expression in human placenta
Syncytin 2 is a newly identified placental membrane protein with fusogenic and immunosuppressive activities. Major facilitator superfamily domain containing 2A (MFSD2A) is the cognate receptor for syncytin 2-mediated cell-cell fusion. Both syncytin 2 and MFSD2A are highly expressed in placenta. Expression of syncytin 2 and MFSD2A genes are regulated by the placental transcription factor GCM1 in placental cells.
GCM1 regulation of the expression of syncytin 2 and its cognate receptor MFSD2A in human placenta.
Gene expression in human brain
Mfsd2a is the major transporter for DHA (Docosahexaenoic acid is an omega-3 fatty acid that is essential for normal brain growth and cognitive function) uptake into brain. Mfsd2a is found to be expressed exclusively in endothelium of the blood–brain barrier of micro-vessels. Lipidomic analysis indicates that Mfsd2a deficient (Mfsd2a-knockout)mice showmarkedly reduced levels of DHA in brain accompanied by neuronal cell loss in hippocampus and cerebellum, as well as cognitive deficits and severe anxiety,and microcephaly. Unexpectedly, cell-based studies indicate that Mfsd2a transports DHA in the form of lysophosphatidylcholine (LPC), but not unesterified fatty acid, in a sodium-dependent manner. Notably, Mfsd2a transports common plasma LPCs carrying long-chain fatty acids such LPC oleate and LPC palmitate, but not LPCs with less than a 14-carbon acyl chain.
Mfsd2a is a transporter for the essential omega-3 fatty acid docosahexaenoic acid
Gene expression in brown adipose tissue and liver
Mfsd2a is expressed in many tissues and is highly induced in liver and BAT (brown adipose tissue) during fasting. Mfsd2a displays an oscillatory expression profile in BAT and liver, consistent with a circadian rhythm. Although the basal level of Mfsd2a expression is relatively low in mouse BAT, it is greatly induced during cold-induced thermogenesis and after treatment with betaAR (beta-adrenergic receptor) agonists. This induction is totally abolished in beta-less (betaAR-deficient) mice. These findings indicate that Mfsd2a is greatly up-regulated in BAT during thermogenesis and that its induction is controlled by the betaAR signalling pathway. Mfsd2a plays therefore a role in adaptive thermogenesis.
Mfsd2a encodes a novel major facilitator superfamily domain-containing protein highly induced in brown adipose tissue during fasting and adaptive thermogenesis.
MFSD2A in lung tumor
A 106-kb linkage disequilibrium (LD) block on chromosome 1p34, which includes the TRIT1, MYCL1, and MFSD2A genes, is associated with lung cancer prognosis and survival. MYCL1 expression is not detected in normal or tumor tissue. Both the TRIT1 and MFSD2A genes are downregulated in lung adenocarcinomas (ADCA), whereas overexpression of either gene has tumor-suppressor effects. The MFSD2A gene was also strongly downregulated in a panel of non-small cell lung cancer (NSCLC) cell lines, where it inhibits cell adhesion and migration when overexpressed. Thus, available data suggest that downregulation of MFSD2A plays a role in lung tumor progression. Since functional polymorphisms in the promoter region may affect mRNA levels of target genes by altering transcription factor (TF) binding sites, single-nucleotide polymorphisms (SNPs) mapping in the MFSD2A 5’ region may play a role in altering MFSD2A promoter activity.
A 5'-region polymorphism modulates promoter activity of the tumor suppressor gene MFSD2A.
MFSD2A as possible mediator of pre-eclampsia
Syncytin-1 and Syncytin-2, seem to play an active role through their fusogenic capacity [1e7]. Both HERV Env proteins have in fact been shown to be reduced in their expression in placentas from patients suffering from pre-eclampsia (PE), a placental pathology often associated with a delay in intrauterine growth of the fetus and responsible for maternal and perinatal morbidity. This association might be related to the implication of these proteins in trophoblast fusion, as previous studies have shown that this disorder is characterized by abnormal placentation and reduced fusion of cultured primary trophoblasts.
MFSD2a, the Syncytin-2 receptor, is important for trophoblast fusion.
MFSD2A in gastric cancer
Genetic polymorphisms in the region of three neighboring genes, TRIT1, MYCL1 and MFSD2A, were associated with the risk and clinicopathological features of gastric cancer. MFSD2A rs4233508 T>C CC genotype was associated with an increased risk of gastric cancer in younger patients and an increased risk of moderately/well-differentiated intestinal-type gastric cancer; rs11581557, rs12083239 and rs2172362 or rs230310 were associated with lymph node metastasis, Lauren’s classification and tumor site, respectively; and the presence of a haplotype was related to lymph node metastasis and tumor site in gastric cancer. In summary some representative tSNPs and haplotypes in the TRIT1, MYCL1 and MFSD2A region are significantly associated with the development and progression of gastric cancer in a Chinese population.
Association of polymorphisms and haplotype in the region of TRIT1, MYCL1 and MFSD2A with the risk and clinicopathological features of gastric cancer in a southeast Chinese population.