Alternative titles; symbols
HGNC Approved Gene Symbol: FOLR1
SNOMEDCT: 711403001;
Cytogenetic location: 11q13.4 Genomic coordinates (GRCh38) : 11:72,189,709-72,196,323 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q13.4 | Neurodegeneration due to cerebral folate transport deficiency | 613068 | Autosomal recessive | 3 |
The FOLR1 gene encodes the adult folate receptor, or folate-binding protein (FBP), which has a high affinity for folic acid and for several reduced folic acid derivatives, and mediates delivery of 5-methyltetrahydrofolate to the interior of cells. Membrane-bound and soluble forms of a high-affinity folate binding protein have been found in kidney, placenta, serum, milk, and in several cell lines. The 2 forms have similar binding characteristics for folates, are immunologically cross-reactive, and, based upon limited amino acid sequence data, are nearly identical. There may be a precursor-product relationship between the membrane and soluble forms, the membrane form having additional amino acid residues and greater molecular weight. The membrane form has been shown to mediate the transport of folate in cells grown in physiologic concentrations of folate (Lacey et al., 1989). There is also a distinct fetal folate receptor (FOLR2; 136425).
Lacey et al. (1989) constructed a cDNA library from a human carcinoma cell line that abundantly expressed the membrane form of the folate receptor. A nearly full-length cDNA for the folate binder was isolated. The deduced amino acid sequence was not consistent with a typical membrane-spanning domain, but rather with a signal for anchoring via a glycosyl-phosphatidylinositol linkage. Release of the binder with a phosphatidylinositol-specific phospholipase C supported this hypothesis.
Elwood (1989) isolated FBP cDNAs by screening placental and nasopharyngeal epidermoid carcinoma (KB) cell line cDNA libraries with oligonucleotide probes based on the sequence of purified membrane-associated FBP. The predicted 257-amino acid protein contains the entire determined amino acid sequence of soluble FBP from both bovine and human milk and has a putative signal peptide and a membrane-anchoring domain. Northern blot analysis revealed that FBP is expressed as a 1.1-kb mRNA in human KB cells, placenta, thymic epithelium, and brain, but not in liver. In vitro translation of the cDNAs yielded a polypeptide that was immunoprecipitated by anti-soluble-FBP antibodies.
Campbell et al. (1991) isolated a cDNA encoding the ovarian cancer-associated antigen by monoclonal antibody MOv18 and demonstrated that it is the same as folate-binding protein. Southern hybridization showed evidence of a family of related genes and/or pseudogenes. Campbell et al. (1991) also identified an MspI and 2 PstI polymorphisms.
By real-time PCR analysis, Steinfeld et al. (2009) showed highest expression of FOLR1 in the choroid plexus compared to other known folate transporters. They concluded that FOLR1 is the major human folate transporter across the blood-brain barrier, and is most crucial for cerebral folate supply. Significant expression FOLR1 was also found in kidney.
Elwood et al. (1997) reported that the FOLR1 gene is composed of 7 exons spanning 6.7 kb. There was heterogeneity in the 5-prime region of FOLR1 cDNAs due to the presence of at least 2 promoters (P1 and P4), multiple transcription start sites, and alternative splicing of exons encoding the 5-prime untranslated region. The 2 promoters showed tissue-specificity: most transcripts in cerebellum and kidney originated from P1, while most transcripts in KB cells and lung originated from P4.
By the analysis of a panel of somatic cell hybrids and by use of a cDNA containing almost the entire coding portion of the FOLR gene, Bowcock et al. (1991) demonstrated that the gene is located on chromosome 11. They also demonstrated 2 independent RFLPs, one of which was shown also to map to chromosome 11. By in situ hybridization, they localized the FOLR gene to 11q13. No recombination was observed between FOLR and INT2 (164950); maximum lod = 8.51 at theta = 0.00. FOLR, but not INT2, hybridized to DNA from a hybrid cell line that retained 11q13-qter. This placed FOLR distal to INT2 and close to the breakpoint. Campbell et al. (1991) mapped the FOLR1 gene to chromosome 11q13.3-q14.1 by fluorescence in situ hybridization. Using fluorescence in situ hybridization, Ragoussis et al. (1992) refined the assignment of the FOLR1 locus to 11q13.3-q13.5, telomeric of the FGF3 locus (164950) which is also located at 11q13.
To identify cellular entry factors employed by the Marburg (MBG) virus, Chan et al. (2001) used noninfectible cells transduced with an expression library and challenged them with a selectable pseudotype virus packaged by MBG glycoproteins. A cDNA encoding FOLR1 was recovered from cells exhibiting reconstitution of viral entry. A FOLR1 cDNA was also recovered in a similar strategy employing Ebola (EBO) pseudotypes. FOLR1 expression in Jurkat cells facilitated MBG or EBO entry, and FR-blocking reagents inhibited infection by MBG or EBO. Finally, FOLR1 bound cells expressing MBG or EBO glycoproteins and mediated syncytia formation triggered by MBG glycoproteins. The authors concluded that FOLR1 is a significant cofactor for cellular entry for MBG and EBO viruses.
Sun and Antony (1996) presented evidence that a specific interaction between an 18-bp cis element in the 5-prime UTR of FOLR1 mRNA and a 46-kD cytosolic trans factor is critical for translation of FOLR1. Furthermore, Xiao et al. (2001) presented evidence that the folate receptor mRNA-binding trans factor is heterogeneous nuclear ribonucleoprotein E1 (hnRNPE1). Antony et al. (2004) reported that the marked upregulation of folate receptors observed in folate deficiencies was mediated at the translational level by the metabolite homocysteine, which accumulates in folate deficiency and increases the interaction of the cis element and hnRNPE1, which, in turn, results in increased biosynthesis of folate receptors. They stated that this was the first time that a mechanistic linkage between substrate build-up from perturbed folate metabolism secondary to nutritional folate deficiency and the coordinated upregulation of a protein that is integrally involved in folate metabolism had been characterized at the translational level.
Using microarray analysis, Menzies et al. (2009) found that thousands of genes were upregulated during periods of increased milk protein production in lactating cow, tammar wallaby, and Cape fur seal, but that only 6 genes were commonly upregulated in all 3 species. Of these 6, Folr1 showed the greatest change in expression, suggesting that Folr1 is an important regulator of milk protein synthesis.
Neurodegeneration due to Cerebral Folate Transport Deficiency
In 2 German sibs with neurodegeneration due to cerebral folate transport deficiency (NCFTD; 613068), Steinfeld et al. (2009) identified compound heterozygosity for 2 mutations in the FOLR1 gene (Q118X, 136430.0001 and C175X, 136430.0002). An unrelated Italian girl with the disorder was homozygous for an 18-bp duplication (136430.0003) in the FOLR1 gene. The disorder was characterized by onset beyond 2 years of life of severe developmental regression, movement disturbances, epilepsy, and leukodystrophy. Brain MRI showed hypomyelination, and MRS showed decreased white matter choline and inositol. Treatment with oral folate resulted in amelioration and prevention of symptoms.
Neural Tube Defects
To examine the association between the FOLR1 gene and susceptibility to neural tube defects (NTD; 601634), Barber et al. (1998) searched for mutations in this gene in 3 separate studies. The initial screening was performed by single-strand conformation polymorphism (SSCP) analysis of DNA from a population-based case-control study of neural tube defects in California. In a second study, the authors analyzed the DNA sequence of exons 5 and 6 in a group of 50 persons with neural tube defects. Finally, dideoxy fingerprinting was used to screen a population-based case-control sample of 219 persons. No polymorphism was detected in any of the 4 exons examined.
De Marco et al. (2000) found variation in the FOLR1 gene in 4 unrelated patients out of 50 with sporadic NTD. The 4 had de novo insertions of pseudogene-specific mutations in exon 7 and the 3-prime UTR of the FOLR1 gene, arising by microconversion events. All of the substitutions affected the carboxy-terminal amino acid membrane tail or the GPI anchor region of the nascent protein. Among 150 control individuals, they identified 1 infant with a gene conversion event within the FOLR1 coding region.
Periconceptional folic acid supplementation reduces the occurrence of several human congenital malformations, including craniofacial, heart, and neural tube defects (Czeizel and Dudas, 1992; Werler et al., 1993; Shaw et al., 1994). Although the underlying mechanism is unknown, there may be a maternal-to-fetal folate transport defect or an inherent fetal biochemical disorder that is neutralized by supplementation. To determine whether folic acid-binding protein-1 is involved in maternal-to-fetal folate transport, Piedrahita et al. (1999) inactivated the gene (symbolized Folbp1 in that species) in mice. They also produced mice lacking Folbp2 (FOLR2; 136425), another member of the folate receptor family that is GPI-anchored but binds folate poorly. Folbp2 -/- embryos developed normally, but Folbp1 -/- embryos had severe morphogenetic abnormalities and died in utero by embryonic day 10. Supplementing pregnant Folbp1 +/- dams with folinic acid reversed this phenotype in nullizygous pups. The results suggested that Folbp1 has a critical role in folate homeostasis during development, and that functional defects in the human homolog, FOLR1, may contribute to similar defects in humans.
In 2 German sibs with neurodegeneration due to cerebral folate transport deficiency (NCFTD; 613068), Steinfeld et al. (2009) identified compound heterozygosity for mutation in the FOLR1 gene: a 352C-T transition in exon 3, resulting in a gln118-to-ter (Q118X) substitution, and a 525C-A transversion in exon 5, resulting in a cys175-to-ter (C175X; 136430.0002) substitution. Neither mutation was identified in 210 control alleles. The older sib was severely handicapped, wheelchair-bound, and had refractory seizures that improved after folate treatment. The younger sib was treated with folate at the onset of symptoms and completely recovered. Semiquantitative PCR analysis did not detect mRNA transcripts from either allele, consistent with nonsense-mediated mRNA decay. Binding studies demonstrated a loss of folate receptor-specific folate binding to patient fibroblasts; folate binding could be rescued by retroviral transfection of fibroblasts with wildtype FOLR1.
For discussion of the cys175-to-ter (C175X) mutation in the FOLR1 gene that was found in compound heterozygous state in sibs with neurodegeneration due to cerebral folate transport deficiency (NCFTD; 613068) by Steinfeld et al. (2009), see 136430.0002.
In an Italian girl with neurodegeneration due to cerebral folate transport deficiency (NCFTD; 613068), Steinfeld et al. (2009) identified a homozygous 18-bp in-frame duplication at nucleotide 130 in exon 2 of the FOLR1 gene, resulting in an insertion of 6 amino acids. The mother and father were both heterozygous for the duplication, which was not identified in 210 control alleles. In vitro functional expression studies showed that the duplication resulted in decreased production of mutant protein, mislocalization of the protein to intracellular compartments, and an almost complete loss of folate receptor function. The authors suggested that this mutation likely causes major misfolding and subsequent premature degradation of the mutant protein. Although the patient was severely handicapped at age 5 years, treatment with oral folate resulted in some clinical improvement. Brain MRI showed severely disturbed myelination affecting the periventricular and subcortical white matter.
Antony, A. C., Tang, Y.-S., Khan, R. A., Biju, M. P., Xiao, X., Li, Q.-J., Sun, X.-L., Jayaram, H. N., Stabler, S. P. Translational upregulation of folate receptors is mediated by homocysteine via RNA-heterogeneous nuclear ribonucleoprotein E1 interactions. J. Clin. Invest. 113: 285-301, 2004. [PubMed: 14722620] [Full Text: https://doi.org/10.1172/JCI11548]
Barber, R. C., Shaw, G. M., Lammer, E. J., Greer, K. A., Biela, T. A., Lacey, S. W., Wasserman, C. R., Finnell, R. H. Lack of association between mutations in the folate receptor-alpha gene and spina bifida. Am. J. Med. Genet. 76: 310-317, 1998. Note: Erratum: Am. J. Med. Genet. 79: 231 only, 1998. [PubMed: 9545095]
Bowcock, A. M., Lacey, S., Saltman, D., Mohandas, T. K., Kamen, B. A., Taggart, R. T. Localization of the folate receptor gene to chromosome 11q13. (Abstract) Cytogenet. Cell Genet. 58: 1955 only, 1991.
Campbell, I. G., Jones, T. A., Foulkes, W. D., Trowsdale, J. Folate-binding protein is a marker for ovarian cancer. Cancer Res. 51: 5329-5338, 1991. [PubMed: 1717147]
Chan, S. Y., Empig, C. J., Welte, F. J., Speck, R. F., Schmaljohn, A., Kreisberg, J. F., Goldsmith, M. A. Folate receptor-alpha is a cofactor for cellular entry by Marburg and Ebola viruses. Cell 106: 117-126, 2001. [PubMed: 11461707] [Full Text: https://doi.org/10.1016/s0092-8674(01)00418-4]
Czeizel, A. E., Dudas, I. Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation. New Eng. J. Med. 327: 1832-1835, 1992. [PubMed: 1307234] [Full Text: https://doi.org/10.1056/NEJM199212243272602]
De Marco, P., Moroni, A., Merello, E., de Franchis, R., Andreussi, L., Finnell, R. H., Barber, R. C., Cama, A., Capra, V. Folate pathway gene alterations in patients with neural tube defects. Am. J. Med. Genet. 95: 216-223, 2000. [PubMed: 11102926] [Full Text: https://doi.org/10.1002/1096-8628(20001127)95:3<216::aid-ajmg6>3.0.co;2-f]
Elwood, P. C., Nachmanoff, K., Saikawa, Y., Page, S. T., Pacheco, P., Roberts, S., Chung, K.-N. The divergent 5-prime 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: 1467-1478, 1997. [PubMed: 9063895] [Full Text: https://doi.org/10.1021/bi962070h]
Elwood, P. C. Molecular cloning and characterization of the human folate-binding protein cDNA from placenta and malignant tissue culture (KB) cells. J. Biol. Chem. 264: 14893-14901, 1989. [PubMed: 2768245]
Lacey, S. W., Sanders, J. M., Rothberg, K. G., Anderson, R. G. W., Kamen, B. A. Complementary DNA for the folate binding protein correctly predicts anchoring to the membrane by glycosyl-phosphatidylinositol. J. Clin. Invest. 84: 715-720, 1989. [PubMed: 2527252] [Full Text: https://doi.org/10.1172/JCI114220]
Menzies, K. K., Lefevre, C., Sharp, J. A., Macmillan, K. L., Sheehy, P. A., Nicholas, K. R. A novel approach identified the FOLR1 gene, a putative regulator of milk protein synthesis. Mammalian Genome 20: 498-503, 2009. [PubMed: 19669235] [Full Text: https://doi.org/10.1007/s00335-009-9207-4]
Piedrahita, J. A., Oetama, B., Bennett, G. D., van Waes, J., Kamen, B. A., Richardson, J., Lacey, S. W., Anderson, R. G. W., Finnell, R. H. Mice lacking the folic acid-binding protein Folbp1 are defective in early embryonic development. Nature Genet. 23: 228-232, 1999. [PubMed: 10508523] [Full Text: https://doi.org/10.1038/13861]
Ragoussis, J., Senger, G., Trowsdale, J., Campbell, I. G. Genomic organization of the human folate receptor genes on chromosome 11q13. Genomics 14: 423-430, 1992. [PubMed: 1330883] [Full Text: https://doi.org/10.1016/s0888-7543(05)80236-8]
Shaw, G. M., Jensvold, N. G., Wasserman, C. R., Lammer, E. J. Epidemiologic characteristics of phenotypically distinct neural tube defects among 0.7 million California births, 1983-1987. Teratology 49: 143-149, 1994. [PubMed: 8016745] [Full Text: https://doi.org/10.1002/tera.1420490210]
Steinfeld, R., Grapp, M., Kraetzner, R., Dreha-Kulaczewski, S., Helms, G., Dechent, P., Wevers, R., Grosso, S., Gartner, J. Folate receptor alpha defect causes cerebral folate transport deficiency: a treatable neurodegenerative disorder associated with disturbed myelin metabolism. Am. J. Hum. Genet. 85: 354-363, 2009. [PubMed: 19732866] [Full Text: https://doi.org/10.1016/j.ajhg.2009.08.005]
Sun, X.-L., Antony, A. C. Evidence that a specific interaction between an 18-base cis-element in the 5-prime-untranslated region of human folate receptor-alpha mRNA and a 46-kDa cytosolic trans-factor is critical for translation. J. Biol. Chem. 271: 25539-25547, 1996. [PubMed: 8810326]
Werler, M. M., Shapiro, S., Mitchell, A. A. Periconceptional folic acid exposure and risk of occurrent neural tube defects. JAMA 269: 1257-1261, 1993. [PubMed: 8437302]
Xiao, X., Tang, Y.-S., Mackins, J. Y., Sun, X.-L., Jayaram, H. N., Hansen, D. K., Antony, A. C. Isolation and characterization of a folate receptor mRNA-binding trans-factor from human placenta: evidence favoring identity with heterogeneous nuclear ribonucleoprotein E1. J. Biol. Chem. 276: 41510-41517, 2001. [PubMed: 11527973] [Full Text: https://doi.org/10.1074/jbc.M106824200]