Alternative titles; symbols
HGNC Approved Gene Symbol: SLC19A2
SNOMEDCT: 237617006;
Cytogenetic location: 1q24.2 Genomic coordinates (GRCh38) : 1:169,463,909-169,485,970 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q24.2 | Thiamine-responsive megaloblastic anemia syndrome | 249270 | Autosomal recessive | 3 |
The SLC19A2 gene encodes a functional thiamine transporter (Fleming et al., 1999).
By positional cloning, Labay et al. (1999) identified the SLC19A2 gene within the critical region of the locus for thiamine-responsive megaloblastic anemia syndrome (TRMA; 249270) on chromosome 1q23.3.
Due to its homology with SLC19A1 (600424), a reduced folate carrier protein, Diaz et al. (1999) identified the SLC19A2 gene in the critical region 1q23.2-q23.3 and cloned the entire SLC19A2 coding region by screening a human fetal brain cDNA library. The SLC19A2 gene encodes a protein of 497 amino acids predicted to have 12 transmembrane domains. Northern blot analysis detected a 4-kb transcript in all tissues tested, most abundantly in skeletal and cardiac muscle.
Dutta et al. (1999) independently cloned SLC19A2, which they called THT1, from a placenta cDNA library. The deduced 497-amino acid protein has a calculated molecular mass of 55.4 kD. It contains 12 putative transmembrane domains, with cytosolic N and C termini. THT1 also has 2 N-glycosylation sites in putative extracellular domains, 3 phosphorylation sites in putative intracellular domains, and a 17-amino acid G protein-coupled receptor signature sequence. The THT1 protein shares 40% amino acid identity with the reduced folate transporter RFC1 (SLC19A1). Northern blot analysis detected variable expression of a 3.8-kb transcript in most tissues examined, with highest expression in skeletal muscle, followed by placenta, heart, liver, and kidney.
Subramanya et al. (2011) found expression of both the Slc19a2 and Slc19a3 genes in rat pancreatic acinar cells, with Slc19a2 showing higher expression.
Independently, Labay et al. (1999) and Dutta et al. (1999) found that the SLC19A2 gene contains 6 exons and spans approximately 22.5 kb.
By assaying transfected HeLa cells, Dutta et al. (1999) showed that THT1 mediated thiamine transport. THT1 did not transport any other organic cation tested, and it did not transport any folate tested. Transport of thiamine by THT1 was independent of Na(+) and showed a pH optimum of 8.0 for recombinant THT1. In contrast, endogenous thiamine transport in HeLa cells kept increasing even when pH was increased to 8.5.
By transfecting fluorescence-tagged deletion constructs of SLC19A2 into epithelial cell lines, Subramanian et al. (2003) determined that the N-terminal domain and the sequence between transmembrane domain 6 and the C-terminal domain were required for proper plasma membrane targeting of SLC19A2. Inhibitor studies showed that SLC19A2 was transported to the plasma membrane via microtubule-based intracellular vesicles.
Diaz et al. (1999) mapped the SLC19A2 gene to chromosome 1q23.2-q23.3.
In all affected individuals in 6 families segregating thiamine-responsive megaloblastic anemia syndrome (TRMA), also known as thiamine metabolism dysfunction syndrome-1 (THMD1; 249270), Labay et al. (1999) identified homozygous mutations in the SLC19A2 gene (see, e.g., 603941.0001-603941.0004).
Fleming et al. (1999) used a candidate gene approach to identify putative thiamine transporters in the 1q23.3 critical region for TRMA and found mutations in the SLC19A2 gene in 2 families with TRMA, 1 Alaskan, studied by Neufeld et al. (1997), and 1 Turkish-Kurdish living in Switzerland (603941.0005 and 603941.0006).
Among 4 Iranian families with TRMA, Diaz et al. (1999) identified 2 frameshift mutations in exon 2, a 1-bp insertion and a 2-bp deletion, of the SLC19A2 gene (603941.0007-603941.0008).
Raz et al. (2000) summarized knowledge on mutations in the SLC19A2 gene in TRMA patients and identified 4 novel mutations.
To generate a mouse model of TRMA, Oishi et al. (2002) disrupted the Slc19a2 gene in mice by homologous recombination in embryonic stem cells. Erythrocytes from the null mice lacked the high-affinity component of thiamine transport. On a thiamine-free diet, null mice developed diabetes mellitus with reduced insulin (176730) secretion and an enhanced response to insulin. The diabetes mellitus resolved after 6 weeks of thiamine repletion. Auditory-evoked brainstem response thresholds were markedly elevated in null mice on a thiamine-free diet, but were normal in wildtype mice treated on that diet as well as thiamine-fed-null mice. Bone marrows from thiamine-deficient null mice were abnormal, with a megaloblastosis affecting the erythroid, myeloid, and megakaryocyte lines.
Liberman et al. (2006) found that Slc19a2-knockout mice on a low thiamine diet developed hearing loss, as shown by 40- to 60-dB threshold elevations on auditory brainstem response (ABR). However, there were only 10- to 20-dB elevations by otoacoustic emission (OAE) measures. Histologic studies showed selective loss of inner hair cells in the cochlea after 1 to 2 weeks on low thiamine. There was significantly greater inner than outer hair cell loss after a longer period of time. Wildtype mice on a low thiamine diet showed no hearing deficit. These results suggested that Slc19a2-null mice have an auditory neuropathy phenotype, in which cochlear neural responses are significantly more reduced than the reduction in cochlear amplifier function. The selective loss of inner hair cells was a rare type of sensorineural histopathology.
Reidling et al. (2010) found that Slc19a3 (606152)-null mice had reduced uptake of intestinal thiamine and decreased serum thiamine compared to wildtype mice. However, intestinal uptake of thiamine in Slc19a2-null mice was not significantly different from that of wildtype mice. Moreover, the level of expression of Slc19a2 was not altered in the intestine of Slc19a3-null mice, but the level of expression of Slc19a3 was upregulated in the intestine of Slc19a2-null mice, thus compensating for the defect. The findings suggested that Slc19a3 is required for normal uptake of thiamine in the intestine, and can fulfill normal levels of uptake in conditions associated with Slc19a2 dysfunction.
Subramanya et al. (2011) found expression of both the Slc19a2 and Slc19a3 (606152) genes in rat pancreatic acinar cells. Chronic alcohol feeding of rats resulted in significant inhibition of carrier-mediated thiamine uptake by pancreatic acinar cells, and was associated with a significant reduction in expression of Slc19a2 and Slc19a3 at the protein and mRNA levels. The results demonstrated that thiamine uptake by pancreatic acinar cells occurs through a carrier-mediated process, and that thiamine transporters are expressed in these cells.
In a Pakistani family and in a Japanese family, Labay et al. (1999) found that thiamine-responsive megaloblastic anemia syndrome (TRMA; 249270) was due to a homozygous 484C-T transition in exon 2 of the SLC19A2 gene predicted to cause an arg162-to-ter protein change.
In affected members of 2 Israeli families with thiamine-responsive megaloblastic anemia syndrome (TRMA; 249270), Labay et al. (1999) found a homozygous 1-bp deletion (724delC) in exon 2 of the SLC19A2 gene, causing a frameshift at codon 242 and creating a stop at codon 259.
In an Italian family, Labay et al. (1999) found a homozygous 515G-A transition in exon 2 of the SLC19A2 gene, predicting a gly172-to-asp amino acid change, as the cause of thiamine-responsive megaloblastic anemia (TRMA; 249270).
In an Indian family with thiamine-responsive megaloblastic anemia syndrome (TRMA; 249270), Labay et al. (1999) found a homozygous 750G-A transition in exon 2 of the SLC19A2 gene leading to a nonsense mutation, trp250 to ter, in the protein product.
In affected members from an Alaskan kindred with thiamine-responsive megaloblastic anemia syndrome (TRMA; 249270) studied by Neufeld et al. (1997), Fleming et al. (1999) found a 1-bp (thymine) deletion at position 885 of the cDNA sequence of the SLC19A2 gene. The proband was homozygous for the deletion resulting in a frameshift and the introduction of a premature stop codon. In the heterozygotes, the reading frame was lost at position 885.
In a patient with thiamine-responsive megaloblastic anemia syndrome (TRMA; 249270) from a Swiss-Kurdish kindred, Fleming et al. (1999) found deletion of GT at positions 1147-1148 of the cDNA sequence of the SLC19A2 gene in homozygous state. The reading frame was lost at position 1148 in a heterozygote. The deletion resulted in a frameshift and immediate stop codon.
In affected members of an Iranian family with thiamine-responsive megaloblastic anemia syndrome (TRMA; 249270), Diaz et al. (1999) found insertion of an adenine between nucleotide 242 and 243 in exon 2 of the SLC19A2 cDNA, introducing a stop codon at codon 52.
In affected members of an Iranian family with thiamine-responsive megaloblastic anemia syndrome (TRMA; 249270), Diaz et al. (1999) identified a 2-bp deletion involving 429T and 430T of the SLC19A2 gene. Three affected members of the family were studied and found to be homozygous. Two sets of parents and 1 unaffected sib were heterozygous for the mutation.
In a girl with thiamine-responsive megaloblastic anemia syndrome (TRMA; 249270), Scharfe et al. (2000) reported a G-to-A transition at nucleotide 1074 in exon 4 of the SLC19A2 gene, resulting in a trp358-to-ter mutation. In addition to TRMA, the girl had short stature, hepatosplenomegaly, retinal degeneration, and a 2-cm lesion in the parietal lobe without any neurologic correlates. Biochemical analyses of muscle and skin biopsies before thiamine supplementation showed a severe deficiency of pyruvate dehydrogenase and complex I of the respiratory chain. These normalized after thiamine supplementation.
In an African American female with thiamine-responsive megaloblastic anemia syndrome (TRMA; 249270) associated with thyroid disease and retinitis pigmentosa, Lagarde et al. (2004) identified a homozygous 152C-T transition in exon 1 of the SLC19A2 gene, resulting in a cys152-to-thr (C152T) mutation. The patient presented at 12 months of age with paroxysmal atrial tachycardia and hepatosplenomegaly. One month later, she developed diabetes mellitus requiring intermittent insulin therapy. At 2.5 years of age, profound sensorineural hearing loss was discovered. By 4 years of age, daily insulin therapy was instituted. She developed optic atrophy, retinitis pigmentosa, and visual impairment by 12 years of age with severe restriction of peripheral vision by 16 years. At age 19 years a thiamine-responsive normocytic anemia was discovered. A diagnosis of autoimmune thyroiditis was made at the age of 20 years. With oral thiamine therapy, her insulin requirement decreased.
Diaz, G. A., Banikazemi, M., Oishi, K., Desnick, R. J., Gelb, B. D. Mutations in a new gene encoding a thiamine transporter cause thiamine-responsive megaloblastic anaemia syndrome. Nature Genet. 22: 309-312, 1999. [PubMed: 10391223] [Full Text: https://doi.org/10.1038/10385]
Dutta, B., Huang, W., Molero, M., Kekuda, R., Leibach, F. H., Devoe, L. D., Ganapathy, V., Prasad, P. D. Cloning of the human thiamine transporter, a member of the folate transporter family. J. Biol. Chem. 274: 31925-31929, 1999. [PubMed: 10542220] [Full Text: https://doi.org/10.1074/jbc.274.45.31925]
Fleming, J. C., Tartaglini, E., Steinkamp, M. P., Schorderet, D. F., Cohen, N., Neufeld, E. J. The gene mutated in thiamine-responsive anaemia with diabetes and deafness (TRMA) encodes a functional thiamine transporter. Nature Genet. 22: 305-308, 1999. [PubMed: 10391222] [Full Text: https://doi.org/10.1038/10379]
Labay, V., Raz, T., Baron, D., Mandel, H., Williams, H., Barrett, T., Szargel, R., McDonald, L., Shalata, A., Nosaka, K., Gregory, S., Cohen, N. Mutations in SLC19A2 cause thiamine-responsive megaloblastic anaemia associated with diabetes mellitus and deafness. Nature Genet. 22: 300-304, 1999. [PubMed: 10391221] [Full Text: https://doi.org/10.1038/10372]
Lagarde, W. H., Underwood, L. E., Moats-Staats, B. M., Calikoglu, A. S. Novel mutation in the SLC19A2 gene in an African-American female with thiamine-responsive megaloblastic anemia syndrome. Am. J. Med. Genet. 125A: 299-305, 2004. [PubMed: 14994241] [Full Text: https://doi.org/10.1002/ajmg.a.20506]
Liberman, M. C., Tartaglini, E., Fleming, J. C., Neufeld, E. J. Deletion of SLC19A2, the high affinity thiamine transporter, causes selective inner hair cell loss and an auditory neuropathy phenotype. J. Assoc. Res. Otolaryng. 7: 211-217, 2006. [PubMed: 16642288] [Full Text: https://doi.org/10.1007/s10162-006-0035-x]
Neufeld, E. J., Mandel, H., Raz, T., Szargel, R., Yandava, C. N., Stagg, A., Faure, S., Barrett, T., Buist, N., Cohen, N. Localization of the gene for thiamine-responsive megaloblastic anemia syndrome, on the long arm of chromosome 1, by homozygosity mapping. Am. J. Hum. Genet. 61: 1335-1341, 1997. [PubMed: 9399900] [Full Text: https://doi.org/10.1086/301642]
Oishi, K., Hofmann, S., Diaz, G. A., Brown, T., Manwani, D., Ng, L., Young, R., Vlassara, H., Ioannou, Y. A., Forrest, D., Gelb, B. D. Targeted disruption of Slc19a2, the gene encoding the high-affinity thiamin transporter Thtr-1, causes diabetes mellitus, sensorineural deafness and megaloblastosis in mice. Hum. Molec. Genet. 11: 2951-2960, 2002. [PubMed: 12393806] [Full Text: https://doi.org/10.1093/hmg/11.23.2951]
Raz, T., Labay, V., Baron, D., Szargel, R., Anbinder, Y., Barrett, T., Rabl, W., Viana, M. B., Mandel, H., Baruchel, A., Cayuela, J.-M., Cohen, N. The spectrum of mutations, including four novel ones, in the thiamine-responsive megaloblastic anemia gene SLC19A2 of eight families. Hum. Mutat. 16: 37-43, 2000. [PubMed: 10874303] [Full Text: https://doi.org/10.1002/1098-1004(200007)16:1<37::AID-HUMU7>3.0.CO;2-9]
Reidling, J. C., Lambrecht, N., Kassir, M., Said, H. M. Impaired intestinal vitamin B1 (thiamin) uptake in thiamin transporter-2-deficient mice. Gastroenterology 138: 1802-1809, 2010. [PubMed: 19879271] [Full Text: https://doi.org/10.1053/j.gastro.2009.10.042]
Scharfe, C., Hauschild, M., Klopstock, T., Janssen, A. J. M., Heidemann, P. H., Meitinger, T., Jaksch, M. A novel mutation in the thiamine responsive megaloblastic anaemia gene SLC19A2 in a patient with deficiency of respiratory chain complex I. J. Med. Genet. 37: 669-673, 2000. [PubMed: 10978358] [Full Text: https://doi.org/10.1136/jmg.37.9.669]
Subramanian, V. S., Marchant, J. S., Parker, I., Said, H. M. Cell biology of the human thiamine transporter-1 (hTHTR1): intracellular trafficking and membrane targeting mechanisms. J. Biol. Chem. 278: 3976-3984, 2003. [PubMed: 12454006] [Full Text: https://doi.org/10.1074/jbc.M210717200]
Subramanya, S. B., Subramanian, V. S., Sekar, V. T., Said, H. M. Thiamin uptake by pancreatic acinar cells: effect of chronic alcohol feeding/exposure. Am. J. Physiol. Gastrointest. Liver Physiol. 301: G896-G904, 2011. [PubMed: 21868632] [Full Text: https://doi.org/10.1152/ajpgi.00308.2011]