Alternative titles; symbols
HGNC Approved Gene Symbol: SLC46A1
SNOMEDCT: 62578003;
Cytogenetic location: 17q11.2 Genomic coordinates (GRCh38) : 17:28,394,642-28,406,592 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q11.2 | Folate malabsorption, hereditary | 229050 | Autosomal recessive | 3 |
Shayeghi et al. (2005) cloned mouse Slc46a1, which they called Hcp1, and identified its human homolog by database analysis. The mouse and human proteins contain 459 amino acids and have 9 predicted transmembrane domains. Northern blot analysis detected prominent Hcp1 expression in mouse duodenum, lower expression in liver and kidney, and no expression in other mouse tissues examined. Immunoelectron microscopy revealed Hcp1 in the brush border membrane and apical cytoplasm of mouse duodenum.
By Northern blot analysis of human tissues, Qiu et al. (2006) identified strong expression of 2.7- and 2.1-kb transcripts in kidney, liver, placenta, small intestine, and spleen, with lower expression in colon and testis, and very low expression in brain, lung, stomach, heart, and muscle. Quantitative PCR of human intestine detected high expression in duodenum, followed by jejunum, ileum, cecum, colon, and rectum.
Sharma et al. (2007) determined that human HCP1 shares 80%, 84%, and 87% amino acid identity with bovine, rat, and mouse Hcp1, respectively. They predicted that bovine Hcp1 has 12 transmembrane domains and intracellular N and C termini, and sequence analysis suggested that this structure is conserved among eukaryotes. RT-PCR detected HCP1 expression in human brain, breast, kidney, prostate, spleen, retina, and retinal pigment epithelium.
Shayeghi et al. (2005) determined that the SLC46A1 gene contains 5 exons.
Shayeghi et al. (2005) stated that the SLC46A1 gene maps to human chromosome 17q11.1 and to mouse chromosome 11B5.
Shayeghi et al. (2005) found that mouse Hcp1 mediated transmembrane uptake of heme in a temperature-dependent and saturable manner following expression in Xenopus oocytes and HeLa cells, and that HCP1 was specific for the porphyrin ring. Exposure of mice to hypoxia, which induces iron absorption, induced Hcp1 mRNA. In iron-deficient mouse duodenum, Hcp1 localized to the brush border membrane with little or no cytoplasmic staining. In contrast, Hcp1 appeared to accumulate in the cytoplasm, with no apical staining, in iron-loaded mice.
Latunde-Dada et al. (2006) showed that HCP1 mediated time- and temperature-dependent heme uptake in transfected Caco-2 intestinal cells. HCP1 mRNA expression increased after differentiation in Caco-2 cells, and this increase correlated with enhanced heme uptake during differentiation. Induction of heme oxygenase-1 (HMOX1; 141250), but not iron or iron chelation, induced HCP1 mRNA.
Qiu et al. (2006) identified PCFT as a proton-coupled high-affinity folate transporter that operates at low pH in the intestine.
Nakai et al. (2007) showed that PCFT expressed transiently in human embryonic kidney cells mediated transport of folate at an extracellular pH of 5.5 in a manner independent of Na+ and insensitive to membrane potential. Transport activity was absent at near-neutral pH. Folate transport was saturable and inhibited by reduced folates, including methotrexate. When expressed in canine kidney cells, PCFT mainly localized at the apical membrane, and cellular accumulation of methotrexate was higher from the apical side than from the basal side. Nakai et al. (2007) concluded that PCFT is responsible for intestinal absorption of folate and reduced folates.
In affected members of a family with hereditary folate malabsorption (229050), Qiu et al. (2006) identified a homozygous mutation in the SLC46A1 gene (611672.0001).
In 5 infants with hereditary folate malabsorption, Zhao et al. (2007) identified 6 different biallelic mutations in the SLC46A1 gene (see, e.g., 611672.0002-611672.0005).
In 2 Puerto Rican sisters with hereditary folate malabsorption (229050) (Geller et al., 2002), Qiu et al. (2006) identified a homozygous G-to-A transition in intron 2 of the SLC46A1 gene, resulting in a splice site mutation and the skipping of exon 3. In vitro functional expression studies showed that the mutant protein was trapped intracellularly and lacked transport function. Each unaffected parent was heterozygous for the mutation.
In an African American boy with hereditary folate malabsorption (229050), Zhao et al. (2007) identified a homozygous 1-bp deletion (194delG) in the SLC46A1 gene, resulting in a frameshift and premature termination. In vitro functional expression studies showed that the mutant protein had no folate transport activity.
In a Turkish girl with hereditary folate malabsorption (229050), Zhao et al. (2007) identified a homozygous 337C-A transversion in the SLC46A1 gene, resulting in an arg113-to-ser (R113S) substitution. In vitro functional expression studies showed that the mutant protein had no folate transport activity. The patient presented at 5 months of age with a history of fever, diarrhea, and convulsions. She was anemic and leukopenic, with a megaloblastic bone marrow and hypoimmunoglobulinemia. Despite treatment with parenteral folate, she had chronic seizures and persistent neurologic defects, including hemiplegia and mental retardation. She had previously been reported by Corbeel et al. (1985).
In a male infant with hereditary folate malabsorption (229050), Zhao et al. (2007) identified compound heterozygosity for 2 mutations in the SLC46A1 gene: a 954C-G transversion, resulting in a ser318-to-arg (S318R) substitution, and a 1126C-T transition, resulting in an arg376-to-trp (R376W; 611672.0005) substitution. The patient was of Spanish/Brazilian/Mexican origin and presented at age 4 months with severe macrocytic anemia and thrombocytopenia. He subsequently developed Pneumocystis carinii pneumonia. He had low serum folate and immunoglobulins. Treatment with folate replacement led to clinical improvement. An older sister had developed pancytopenia at age 3 months and died due to cytomegalovirus pneumonia. In vitro functional expression studies showed that both mutant protein lacked folate transport activity.
For discussion of the arg376-to-trp (R376W) mutation in the SLC46A1 gene that was found in compound heterozygous state in a patient with hereditary folate malabsorption (229050) by Zhao et al. (2007), see 611672.0004.
In a patient with hereditary folate malabsorption (229050), Lasry et al. (2008) identified a homozygous 337C-T transition in exon 2 of the in the SLC46A1 gene, resulting in an arg113-to-cys (R113C) substitution in the first intracellular loop connecting transmembrane helices 2 and 3. In vitro functional expression studies in Chinese hamster ovary (CHO) cells showed that the mutant protein was targeted to the plasma membrane but had significantly impaired folate transport activity. Another mutation at this codon (R113S; 611672.0003) was identified in another patient with the disorder. Bioinformatic analysis showed that the arg113 residue is highly conserved and faces the intramembrane hydrophobic pocket that may be part of a folate translocation pore.
In a Tunisian patient, born of consanguineous parents, with hereditary folate malabsorption (229050), previously reported by Jebnoun et al., 2001, Shin et al. (2011) identified a homozygous 1-bp insertion (17insC) in the SLC46A1 gene, resulting in a frameshift and premature termination and predicted to result in complete loss of protein function.
In an English boy with hereditary folate malabsorption (229050), Shin et al. (2011) identified compound heterozygosity for 2 mutations in the SLC46A1 gene: a 1004C-A transversion in exon 2, resulting in an ala335-to-asp (A335D) substitution, and a 2-bp deletion (204_205delCC; 611672.0009) in exon 1, resulting in a frameshift and early termination. The A335D substitution occurred in the ninth transmembrane domain, and in vitro functional expression assays in Hela cells showed that the mutant protein was inactive with no folate uptake activity. The child developed Pneumocystis jiroveci pneumonia associated with anemia and undetectable plasma folate at age 2 months. He later showed delayed motor development, hyperreflexia, jerky movements, tremor, and proximal muscle wasting. Brain MRI at 3 years 9 months showed a slight delay in myelination. He improved neurologically with treatment, but had mild difficulty in fine motor skills and reading but good math skills. He developed occipital seizures at age 5 years.
For discussion of the 2-bp deletion in the SLC46A1 gene (204_205delCC) that was found in compound heterozygous state in a patient with hereditary folate malabsorption (229050) by Shin et al. (2011), see 611672.0008.
In Turkish sibs with hereditary folate malabsorption, Atabay et al. (2010) identified a homozygous 2-bp deletion (204_205delCC) in exon 1 of the SLC46A1 gene, resulting in a frameshift and premature termination. Low blood and cerebrospinal fluid folate levels were detected at ages 3.5 and 1 month, respectively. Treatment with parenteral 5-formyltetrahydrofolate resulted in normal development by ages 3 and 1 year, respectively.
In an 8-year-old Tunisian boy, born of consanguineous parents, with hereditary folate malabsorption (229050), Shin et al. (2011) identified a homozygous 1012G-C transversion in the SLC46A1 gene, resulting in a gly338-to-arg (G338R) substitution in the ninth transmembrane domain. In vitro functional expression assays in Hela cells showed that the mutant protein was inactive with no folate uptake activity. The patient developed macrocytic anemia with low serum folate at age 2.5 months. He was treated with leucovorin, which corrected the anemia and axial hypertonia. EEG and head CT scan were normal. Two affected sibs had died.
Atabay, B., Turker, M., Ozer, E. A., Mahadeo, K., Diop-Bove, N., Goldman, I. D. Mutation of the proton-coupled folate transporter gene (PCFT-SLC46A1) in Turkish siblings with hereditary folate malabsorption. Pediat. Hemat. Oncol. 27: 614-619, 2010. [PubMed: 20795774] [Full Text: https://doi.org/10.3109/08880018.2010.481705]
Corbeel, L., Van den Berghe, G., Jaeken, J., Van Tornout, J., Eeckels, R. Congenital folate malabsorption. Europ. J. Pediat. 143: 284-290, 1985. [PubMed: 3987728] [Full Text: https://doi.org/10.1007/BF00442302]
Geller, J., Kronn, D., Jayabose, S., Sandoval, C. Hereditary folate malabsorption: family report and review of the literature. Medicine 81: 51-68, 2002. [PubMed: 11807405] [Full Text: https://doi.org/10.1097/00005792-200201000-00004]
Jebnoun, S., Kacem, S., Mokrani, C., Chabchoub, A., Khrouf, N., Zittoun, J. A family study of congenital malabsorption of folate. J. Inherit. Metab. Dis. 24: 749-750, 2001. [PubMed: 11804211] [Full Text: https://doi.org/10.1023/a:1012905823879]
Lasry, I., Berman, B., Straussberg, R., Sofer, Y., Bessler, H., Sharkia, M., Glaser, F., Jansen, F., Drori, S., Assaraf, Y. G. A novel loss-of-function mutation in the proton-coupled folate transporter from a patient with hereditary folate malabsorption reveals that Arg 113 is crucial for function. Blood 112: 2055-2061, 2008. [PubMed: 18559978] [Full Text: https://doi.org/10.1182/blood-2008-04-150276]
Latunde-Dada, G. O., Takeuchi, K., Simpson, R. J., McKie, A. T. Haem carrier protein 1 (HCP1): expression and functional studies in cultured cells. FEBS Lett. 580: 6865-6870, 2006. [PubMed: 17156779] [Full Text: https://doi.org/10.1016/j.febslet.2006.11.048]
Nakai, Y., Inoue, K., Abe, N., Hatakeyama, M., Ohta, K., Otagiri, M., Hayashi, Y., Yuasa, H. Functional characterization of human proton-coupled folate transporter/heme carrier protein 1 heterologously expressed in mammalian cells as a folate transporter. J. Pharm. Exp. Ther. 322: 469-476, 2007. [PubMed: 17475902] [Full Text: https://doi.org/10.1124/jpet.107.122606]
Qiu, A., Jansen, M., Sakaris, A., Min, S. H., Chattopadhyay, S., Tsai, E., Sandoval, C., Zhao, R., Akabas, M. H., Goldman, I. D. Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption. Cell 127: 917-928, 2006. [PubMed: 17129779] [Full Text: https://doi.org/10.1016/j.cell.2006.09.041]
Sharma, S., Dimasi, D., Broer, S., Kumar, R., Della, N. G. Heme carrier protein 1 (HCP1) expression and functional analysis in the retina and retinal pigment epithelium. Exp. Cell Res. 313: 1251-1259, 2007. [PubMed: 17335806] [Full Text: https://doi.org/10.1016/j.yexcr.2007.01.019]
Shayeghi, M., Latunde-Dada, G. O., Oakhill, J. S., Laftah, A. H., Takeuchi, K., Halliday, N., Khan, Y., Warley, A., McCann, F. E., Hider, R. C., Frazer, D. M., Anderson, G. J., Vulpe, C. D., Simpson, R. J., McKie, A. T. Identification of an intestinal heme transporter. Cell 122: 789-801, 2005. [PubMed: 16143108] [Full Text: https://doi.org/10.1016/j.cell.2005.06.025]
Shin, D. S., Mahadeo, K., Min, S. H., Diop-Bove, N., Clayton, P., Zhao, R., Goldman, I. D. Identification of novel mutations in the proton-coupled folate transporter (PCFT-SLC46A1) associated with hereditary folate malabsorption. Molec. Genet. Metab. 103: 33-37, 2011. [PubMed: 21333572] [Full Text: https://doi.org/10.1016/j.ymgme.2011.01.008]
Zhao, R., Min, S. H., Qiu, A., Sakaris, A., Goldberg, G. L., Sandoval, C., Malatack, J. J., Rosenblatt, D. S., Goldman, I. D. The spectrum of mutations in the PCFT gene, coding for an intestinal folate transporter, that are the basis for hereditary folate malabsorption. Blood 110: 1147-1152, 2007. [PubMed: 17446347] [Full Text: https://doi.org/10.1182/blood-2007-02-077099]