Folate receptor 1 explained

Folate receptor 1 (Folate receptor alpha, FOLR1) is a protein that in humans is encoded by the FOLR1 gene.^{[1] [2]}

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

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.^[3]

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.

Clinical significance

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.

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).^[4]

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,^[5] particularly cerebral folate deficiency^[6] schizophrenia and autism spectrum disorder.^[7] Recent studies have shown that these neurodevelopmental disorders can be treated with folinic acid.^[8]

See also

• SLC19A1
• ONX-0801

Further reading

• Henderson GB . Folate-binding proteins . Annual Review of Nutrition . 10 . 319–35 . 1990 . 2166548 . 10.1146/annurev.nu.10.070190.001535 .
• Kelemen LE . The role of folate receptor alpha in cancer development, progression and treatment: cause, consequence or innocent bystander? . International Journal of Cancer . 119 . 2 . 243–50 . July 2006 . 16453285 . 10.1002/ijc.21712 . 1966455 . free .
• Ragoussis J, Senger G, Trowsdale J, Campbell IG . Genomic organization of the human folate receptor genes on chromosome 11q13 . Genomics . 14 . 2 . 423–30 . October 1992 . 1330883 . 10.1016/S0888-7543(05)80236-8 .
• Sadasivan E, Cedeno M, Rothenberg SP . Genomic organization of the gene and a related pseudogene for a human folate binding protein . Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression . 1131 . 1 . 91–4 . May 1992 . 1581364 . 10.1016/0167-4781(92)90103-7 .
• Coney LR, Tomassetti A, Carayannopoulos L, Frasca V, Kamen BA, Colnaghi MI, Zurawski VR . Cloning of a tumor-associated antigen: MOv18 and MOv19 antibodies recognize a folate-binding protein . Cancer Research . 51 . 22 . 6125–32 . November 1991 . 1840502 .
• Lacey SW, Sanders JM, Rothberg KG, Anderson RG, Kamen BA . Complementary DNA for the folate binding protein correctly predicts anchoring to the membrane by glycosyl-phosphatidylinositol . The Journal of Clinical Investigation . 84 . 2 . 715–20 . August 1989 . 2527252 . 548937 . 10.1172/JCI114220 .
• Sadasivan E, Rothenberg SP . The complete amino acid sequence of a human folate binding protein from KB cells determined from the cDNA . The Journal of Biological Chemistry . 264 . 10 . 5806–11 . April 1989 . 10.1016/S0021-9258(18)83621-3 . 2538429 . free .
• Elwood PC . Molecular cloning and characterization of the human folate-binding protein cDNA from placenta and malignant tissue culture (KB) cells . The Journal of Biological Chemistry . 264 . 25 . 14893–901 . September 1989 . 10.1016/S0021-9258(18)63786-X . 2768245 . free .
• Sadasivan E, Rothenberg SP . Molecular cloning of the complementary DNA for a human folate binding protein . Proceedings of the Society for Experimental Biology and Medicine . 189 . 2 . 240–4 . November 1988 . 3194438 . 10.3181/00379727-189-42804 . 36960775 .
• Luhrs CA, Pitiranggon P, da Costa M, Rothenberg SP, Slomiany BL, Brink L, Tous GI, Stein S . 6 . Purified membrane and soluble folate binding proteins from cultured KB cells have similar amino acid compositions and molecular weights but differ in fatty acid acylation . Proceedings of the National Academy of Sciences of the United States of America . 84 . 18 . 6546–9 . September 1987 . 3476960 . 299115 . 10.1073/pnas.84.18.6546 . 1987PNAS...84.6546L . free .
• Yan W, Ratnam M . Preferred sites of glycosylphosphatidylinositol modification in folate receptors and constraints in the primary structure of the hydrophobic portion of the signal . Biochemistry . 34 . 44 . 14594–600 . November 1995 . 7578066 . 10.1021/bi00044a039 .
• Saikawa Y, Price K, Hance KW, Chen TY, Elwood PC . Structural and functional analysis of the human KB cell folate receptor gene P4 promoter: cooperation of three clustered Sp1-binding sites with initiator region for basal promoter activity . Biochemistry . 34 . 31 . 9951–61 . August 1995 . 7632694 . 10.1021/bi00031a018 .
• Prasad PD, Ramamoorthy S, Moe AJ, Smith CH, Leibach FH, Ganapathy V . Selective expression of the high-affinity isoform of the folate receptor (FR-alpha) in the human placental syncytiotrophoblast and choriocarcinoma cells . Biochimica et Biophysica Acta (BBA) - Molecular Cell Research . 1223 . 1 . 71–5 . August 1994 . 8061055 . 10.1016/0167-4889(94)90074-4 .
• Maruyama K, Sugano S . Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides . Gene . 138 . 1–2 . 171–4 . January 1994 . 8125298 . 10.1016/0378-1119(94)90802-8 .
• Elwood PC, Nachmanoff K, Saikawa Y, Page ST, Pacheco P, Roberts S, Chung KN . The divergent 5' termini of the alpha human folate receptor (hFR) mRNAs originate from two tissue-specific promoters and alternative splicing: characterization of the alpha hFR gene structure . Biochemistry . 36 . 6 . 1467–78 . February 1997 . 9063895 . 10.1021/bi962070h .
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S . Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library . Gene . 200 . 1–2 . 149–56 . October 1997 . 9373149 . 10.1016/S0378-1119(97)00411-3 .
• Barber RC, Shaw GM, Lammer EJ, Greer KA, Biela TA, Lacey SW, Wasserman CR, Finnell RH . 6 . Lack of association between mutations in the folate receptor-alpha gene and spina bifida . American Journal of Medical Genetics . 76 . 4 . 310–7 . April 1998 . 9545095 . 10.1002/(SICI)1096-8628(19980401)76:4<310::AID-AJMG6>3.0.CO;2-T .
• Tomassetti A, Bottero F, Mazzi M, Miotti S, Colnaghi MI, Canevari S . Molecular requirements for attachment of the glycosylphosphatidylinositol anchor to the human alpha folate receptor . Journal of Cellular Biochemistry . 72 . 1 . 111–8 . January 1999 . 10025672 . 10.1002/(SICI)1097-4644(19990101)72:1<111::AID-JCB12>3.0.CO;2-1 . 23174724 .

Notes and References

1. Campbell IG, Jones TA, Foulkes WD, Trowsdale J . Folate-binding protein is a marker for ovarian cancer . Cancer Research . 51 . 19 . 5329–38 . October 1991 . 1717147 .
2. Web site: Entrez Gene: FOLR1 folate receptor 1 (adult).
3. Balashova. Olga A.. Visina. Olesya. Borodinsky. Laura N.. 2017-04-15. Folate receptor 1 is necessary for neural plate cell apical constriction during Xenopus neural tube formation. Development. 144. 8. 1518–1530. 10.1242/dev.137315. 0950-1991. 5399658. 28255006.
4. Scaranti M, Cojocaru E, Banerjee S, Banerji U . Exploiting the folate receptor α in oncology . Nature Reviews. Clinical Oncology . 17 . 6 . 349–359 . June 2020 . 32152484 . 10.1038/s41571-020-0339-5 . 212641989 .
5. Frye RE, Slattery JC, Quadros EV . Folate metabolism abnormalities in autism: potential biomarkers . Biomarkers in Medicine . 11 . 8 . 687–699 . August 2017 . 28770615 . 10.2217/bmm-2017-0109 . free .
6. Ramaekers VT, Rothenberg SP, Sequeira JM, Opladen T, Blau N, Quadros EV, Selhub J . Autoantibodies to folate receptors in the cerebral folate deficiency syndrome . The New England Journal of Medicine . 352 . 19 . 1985–91 . May 2005 . 15888699 . 10.1056/NEJMoa043160 . free .
7. Frye RE, Sequeira JM, Quadros EV, James SJ, Rossignol DA . Cerebral folate receptor autoantibodies in autism spectrum disorder . Molecular Psychiatry . 18 . 3 . 369–81 . March 2013 . 22230883 . 3578948 . 10.1038/mp.2011.175 .
8. Frye RE, Slattery J, Delhey L, Furgerson B, Strickland T, Tippett M, Sailey A, Wynne R, Rose S, Melnyk S, Jill James S, Sequeira JM, Quadros EV . 6 . 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 . February 2018 . 27752075 . 5794882 . 10.1038/mp.2016.168 .