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Folate receptor 1

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FOLR1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesFOLR1, FBP, FOLR, Folate receptor 1, folate receptor 1 (adult), folate receptor alpha, FRalpha, NCFTD
External IDsOMIM: 136430; MGI: 95568; HomoloGene: 7322; GeneCards: FOLR1; OMA:FOLR1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

2348

14275

Ensembl

ENSG00000110195

ENSMUSG00000001827

UniProt

P15328

P35846

RefSeq (mRNA)

NM_016730
NM_000802
NM_016724
NM_016725
NM_016729

NM_001252552
NM_001252553
NM_001252554
NM_008034

RefSeq (protein)

NP_000793
NP_057936
NP_057937
NP_057941

NP_001239481
NP_001239482
NP_001239483
NP_032060

Location (UCSC)Chr 11: 72.19 – 72.2 MbChr 7: 101.51 – 101.52 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Folate receptor 1 (Folate receptor alpha, FOLR1) is a protein that in humans is encoded by the FOLR1 gene.[5][6]

The protein encoded by this gene is a member of the folate receptor (FOLR) family. Members of this family have a high affinity for folic acid and for several reduced folic acid derivatives, and mediate delivery of 5-methyltetrahydrofolate to the interior of cells.

Functions

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This receptor is responsible for binding to folic acid and its derivatives, which becomes crucial during fetal development. By adding folate supplementation during pregnancy, neural tube defects in the fetus are prevented. Folate derivatives are necessary for important metabolic processes such as DNA, protein and lipid methylation. More importantly, folate plays a major role in DNA replication and cell division, which are common characteristics of rapid growth. Even though it is unclear how folate affects neural tube formation, scientists are certain that without appropriate folate levels, neural tube defects can develop through human and mice studies. Neural tube defects refer to the improper development of the neural tube by not being sealed correctly. This results in exencephaly or spina bifida, both nervous system abnormalities.[7]

This gene is composed of 7 exons; exons 1 through 4 encode the 5' UTR and exons 4 through 7 encode the open reading frame. Due to the presence of 2 promoters, multiple transcription start sites, and alternative splicing of exons, several transcript variants are derived from this gene. These variants differ in the lengths of 5' and 3' UTR, but they encode an identical amino acid sequence.[6]

Clinical significance

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Schematic model of FRα used as a target in cancer therapy.[8]

FRα, due to its high expression in some tumors, is an attractive therapeutic target for the development of novel anti-cancer agents in order to limit toxic side-effects on off-target tissues.[8]

FRa can be overexpressed by a number of epithelial-derived tumors including ovarian, breast, renal, lung, colorectal, and brain. According to a review published in 2020, elevated expression of FRa was noted in mesotheliomas (72-100% of cases), triple-negative breast cancer (35-68% of cases) and epithelial ovarian cancer (76-89% of cases).[9]

Therefore, antibodies to FRa are being developed for use in targeted therapies, with one example being farletuzumab, in a phase III trial for ovarian cancer. Further, FRa-binding markers have been created in an attempt to visualise FRa-expressing tumors. In 2021, the fluorescent marker pafolacianine was approved for identification of malignant lesions during surgeries.

Autoantibodies to the FRA have been linked to neurodevelopmental diseases,[10] particularly cerebral folate deficiency[11] schizophrenia[11] and autism spectrum disorder.[12] Recent studies have shown that these neurodevelopmental disorders can be treated with folinic acid.[12][13]

Figures

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Crystallographic structure of FRα protein. The folate is in green, the folate binding site is colored in orange. A Cys66Tyr substitution position induced by a pathogenic variant is represented in red while the disulfide bond between Cys66 and Cys109 is in dark blue. Figure from Mafi et al., 2020[14]
Identification of ovarian cancer metastases located on the intestine and mesentery using fluorescence imaging of the folate receptor alpha-binding marker EC17. From Tummers et al., 2016.[15]

See also

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References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000110195 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000001827 – 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. ^ Campbell IG, Jones TA, Foulkes WD, Trowsdale J (October 1991). "Folate-binding protein is a marker for ovarian cancer". Cancer Research. 51 (19): 5329–38. PMID 1717147.
  6. ^ a b "Entrez Gene: FOLR1 folate receptor 1 (adult)".
  7. ^ Balashova OA, Visina O, Borodinsky LN (2017-04-15). "Folate receptor 1 is necessary for neural plate cell apical constriction during Xenopus neural tube formation". Development. 144 (8): 1518–1530. doi:10.1242/dev.137315. ISSN 0950-1991. PMC 5399658. PMID 28255006.
  8. ^ a b Razaghi A, Zickler AM, Spallholz J, Kirsch G, Björnstedt M (June 2021). "Selenofolate inhibits the proliferation of IGROV1 cancer cells independently from folate receptor alpha". Heliyon. 7 (6): e07254. Bibcode:2021Heliy...707254R. doi:10.1016/j.heliyon.2021.e07254. PMC 8209087. PMID 34169173.
  9. ^ Scaranti M, Cojocaru E, Banerjee S, Banerji U (June 2020). "Exploiting the folate receptor α in oncology". Nature Reviews. Clinical Oncology. 17 (6): 349–359. doi:10.1038/s41571-020-0339-5. PMID 32152484. S2CID 212641989.
  10. ^ Frye RE, Slattery JC, Quadros EV (August 2017). "Folate metabolism abnormalities in autism: potential biomarkers". Biomarkers in Medicine. 11 (8): 687–699. doi:10.2217/bmm-2017-0109. PMID 28770615.
  11. ^ a b Ramaekers VT, Rothenberg SP, Sequeira JM, Opladen T, Blau N, Quadros EV, Selhub J (May 2005). "Autoantibodies to folate receptors in the cerebral folate deficiency syndrome". The New England Journal of Medicine. 352 (19): 1985–91. doi:10.1056/NEJMoa043160. PMID 15888699.
  12. ^ a b Frye RE, Sequeira JM, Quadros EV, James SJ, Rossignol DA (March 2013). "Cerebral folate receptor autoantibodies in autism spectrum disorder". Molecular Psychiatry. 18 (3): 369–81. doi:10.1038/mp.2011.175. PMC 3578948. PMID 22230883.
  13. ^ Frye RE, Slattery J, Delhey L, Furgerson B, Strickland T, Tippett M, et al. (February 2018). "Folinic acid improves verbal communication in children with autism and language impairment: a randomized double-blind placebo-controlled trial". Molecular Psychiatry. 23 (2): 247–256. doi:10.1038/mp.2016.168. PMC 5794882. PMID 27752075.
  14. ^ Mafi S, Laroche-Raynaud C, Chazelas P, Lia AS, Derouault P, Sturtz F, Baaj Y, Froget R, Rio M, Benoist JF, Poumeaud F, Favreau F, Faye PA (October 2020). "Pharmacoresistant Epilepsy in Childhood: Think of the Cerebral Folate Deficiency, a Treatable Disease". Brain Sciences. 10 (11): 762. doi:10.3390/brainsci10110762. PMC 7690394. PMID 33105619.
  15. ^ Tummers QR, Hoogstins CE, Gaarenstroom KN, de Kroon CD, van Poelgeest MI, Vuyk J, Bosse T, Smit VT, van de Velde CJ, Cohen AF, Low PS, Burggraaf J, Vahrmeijer AL (May 2016). "Intraoperative imaging of folate receptor alpha positive ovarian and breast cancer using the tumor specific agent EC17". Oncotarget. 7 (22): 32144–55. doi:10.18632/oncotarget.8282. PMC 5078003. PMID 27014973.

Further reading

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