Alternative titles; symbols
HGNC Approved Gene Symbol: SLC19A3
SNOMEDCT: 703522009;
Cytogenetic location: 2q36.3 Genomic coordinates (GRCh38) : 2:227,683,763-227,718,028 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q36.3 | Thiamine metabolism dysfunction syndrome 2 (biotin/thiamine-responsive basal ganglia disease type) | 607483 | Autosomal recessive | 3 |
SLC19A3 encodes a thiamine transporter (Rajgopal et al., 2001).
By EST database searching with the RFC1 (SLC19A1; 600424) protein sequence as query, PCR, and screening of a human placenta cDNA library, Eudy et al. (2000) cloned a full-length SLC19A3 cDNA encoding a 496-amino acid protein. They also cloned the mouse homolog from a kidney cDNA library. Human SLC19A3 shares 39%, 48%, and 68% amino acid sequence identity with human SLC19A1 and SLC19A2 (603941) and mouse Slc19a3, respectively. Northern blot analysis of human tissues detected 3 transcripts of approximately 3.5, 2.6, and 2.0 kb in placenta, kidney, and liver. Highest expression was observed in placenta, with all 3 transcripts exhibiting similar levels of expression. In the liver and kidney, the 3.5-kb transcript was the most abundant. PCR analysis detected SLC19A3 transcripts in almost all tissues tested. Northern blot analysis in mouse tissues detected a single transcript in brain, kidney, lung, small intestine, heart, and testis, with the highest abundance in kidney and brain. PCR analysis identified weak expression of the mouse gene beginning at embryonic day 8.5 which peaked at E19 just prior to parturition.
Kono et al. (2009) found high SLC19A3 expression in human thalamus compared to other brain regions.
Subramanya et al. (2011) found expression of both the Slc19a2 and Slc19a3 genes in rat pancreatic acinar cells, with Slc19a2 showing higher expression.
By radiation hybrid analysis, Eudy et al. (2000) mapped the human SLC19A3 gene to chromosome 2q37 and the mouse homolog to a region showing syntenic homology on chromosome 1.
By assaying transfected HeLa cells, Rajgopal et al. (2001) found that human SLC19A3 mediated transport of radiolabeled thiamine, but not folic acid, pyridoxine, niacin, methotrexate, or other organic cations examined. The pH optimum for thiamine transport was pH 7.4.
In cellular studies, Subramanian et al. (2006) demonstrated that SLC19A3 is a thiamine transporter expressed at the apical surface of polarized cells, but it does not function as a biotin transporter. SLC19A3 was also expressed in human glioma cells.
Biotin-thiamine-responsive basal ganglia disease (BTBGD; 607483), also known as thiamine metabolism dysfunction syndrome-2 (THMD2) or thiamine-responsive encephalopathy, is an autosomal recessive disorder with childhood onset that presents as a subacute encephalopathy and progresses to severe cogwheel rigidity, dystonia, quadriparesis, and eventually death if left untreated. Zeng et al. (2005) stated that all patients diagnosed to that time were of Saudi, Syrian, or Yemeni ancestry, and all had consanguineous parents. Using linkage analysis in 4 families, they mapped the genetic defect to 2q36.3 to a minimum candidate region of approximately 2 Mb on the basis of complete homozygosity. In this segment, each family displayed 1 of 2 different missense mutations that altered the coding sequence of SLC19A3 (606152.0001 and 606152.0002). The mutations were on different haplotypes.
In a Portuguese brother and sister with BTBGD, Debs et al. (2010) identified compound heterozygosity for 2 truncating mutations in the SLC19A3 gene (606152.0005-606152.0006), confirming that the disorder results from loss of function of this transporter. Each unaffected parent was heterozygous for 1 of the mutations. One of the patients only showed a therapeutic response to thiamine.
Kono et al. (2009) reported 2 Japanese brothers with onset of encephalopathy in the second decade of life. Genetic analysis identified compound heterozygous mutations in the SLC19A3 gene (606152.0003-606152.0004) in both brothers. Kono et al. (2009) stated that the phenotype differed from biotin-responsive basal ganglia disease because brain lesions were found in the thalamus and periaqueductal regions, not in the basal ganglia.
In affected patients from 3 families from the Al Hoceima province in northern Morocco with BTBGD manifest as severe infantile-onset fatal encephalopathy and Leigh syndrome (see 256000) on brain imaging, Gerards et al. (2013) identified the same homozygous truncating mutation in the SLC19A3 gene (S7X; 606152.0007). Haplotype analysis indicated a founder effect estimated to have occurred 1,250 to 1,750 years ago. The mutation in the first family was found by a combination of homozygosity mapping and whole-exome sequencing; the mutations in the subsequent families were found by direct sequencing of the SLC19A3 gene in 17 patients with Leigh syndrome.
Reidling et al. (2010) found that Slc19a3-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 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.
Alaskan Husky encephalopathy (AHE), a fatal brain disease in young Alaskan Husky dogs, presents as a multifocal central nervous system deficit with seizures, altered mentation, dysphagia, central blindness, hypermetria, proprioceptive positioning deficits, ataxia, and tetraparesis. Brain imaging shows abnormal intracranial lesions consistent with Leigh syndrome in humans. Vernau et al. (2013) determined that AHE is caused by homozygosity for a 4-bp deletion and a single nucleotide change (c.624insTTGC, c.625C-A) in the Slc19a3.1 gene that is predicted to result in a protein truncation. Heterozygosity for the mutation was found in 15 of 41 healthy Alaskan Husky control dogs, but not in another 187 dogs of different breeds. Canines have 2 paralogs of SLC19A3, Slc19a3.1 and Slc19a3.2, resulting from gene duplication. Slc19a3.1 is primarily expressed in the cerebrum, cerebellum, spinal cord, kidney, and testes, whereas Slc19a3.2 is mainly expressed in the kidney and liver, suggesting tissue-specific expression of these paralogs.
Vernau et al. (2015) found that the cerebral cortex and thalamus of 2 dogs with AHE were severely deficient in thiamine pyrophosphate (TPP)-dependent enzymes compared to controls. These decreases in enzymatic activity were accompanied by decreases in mitochondrial mass, mtDNA copy number, and oxidative phosphorylation, although the latter decreases did not meet the threshold for a mitochondrial respiratory chain disorder. Affected brain tissue also showed evidence of increased oxidative stress. The findings indicated that the phenotype results from a brain-specific thiamine deficiency, leading to brain mitochondrial dysfunction and increased oxidative stress.
In 2 patients with biotin-thiamine-responsive basal ganglia disease (BTBGD; 607483) in a Yemeni family, Zeng et al. (2005) found a homozygous G-to-T change at nucleotide 68 in exon 2 of the SLC19A3 gene, which was predicted to alter a highly conserved glycine at codon 23 to valine (G23V). This mutation was predicted to alter the first transmembrane domain of the SLC19A3 protein.
In canine kidney cells and human duodenal cells, both polarized epithelial cell lines, Subramanian et al. (2006) showed that the G23V mutant protein localized normally to the apical plasma membrane, similar to the wildtype protein, but showed decreased expression. However, cells expressing the mutant SLC19A3 protein had significantly impaired thiamine transport, similar to untransfected cells.
In 3 families, all of Saudi origin, with biotin-thiamine-responsive basal ganglia disease (BTBGD; 607483), Zeng et al. (2005) identified an A-to-G transition at nucleotide position 1264 in exon 5 of the SLC19A3, predicted to result in a substitution of threonine at codon 422 to alanine (T422A).
Eichler et al. (2017) reported a 20-year-old Saudi woman with BTBGD who was homozygous for the T422A mutation in the SLC19A3 gene.
In canine kidney cells and human duodenal cells, both polarized epithelial cell lines, Subramanian et al. (2006) showed that the T422A mutant protein, which is in transmembrane domain 11, localized normally to the apical plasma membrane, similar to the wildtype protein, but showed decreased expression. However, cells expressing the mutant SLC19A3 protein had significantly impaired thiamine transport, similar to untransfected cells.
In 2 Japanese brothers with biotin-thiamine-responsive basal ganglia disease (BTBGD; 607483) characterized by diplopia, seizures, and white matter changes in the thalamus without serum thiamine deficiency, Kono et al. (2009) identified compound heterozygosity for 2 mutations in the SLC19A3 gene: a 218A-G transition in exon 2, resulting in a lys44-to-glu (K44E) substitution, and a 1047G-C transversion in exon 3, resulting in a glu320-to-gln (E320Q; 606152.0004) substitution. These mutations were not present among 192 ethnically matched controls. In vitro functional cellular expression studies showed that most of the K44E-mutant protein was impaired in intracellular transport while remaining normal in the endoplasmic reticulum. The E320Q mutant was identical in cell surface localization to wildtype protein but showed significantly decreased intracellular thiamine uptake activity. Onset of symptoms was in the second decade of life. Both patients also had severe partial complex seizures that were responsive to high-dose thiamine. Magnetic resonance imaging (MRI) of the brain showed high-intensity signals in the bilateral medial thalamus and periaqueductal region, which were characteristic of findings in Wernicke encephalopathy (277730), but there was no history of chronic alcohol use. These changes became normal within 1 month after treatment. Subacute ophthalmoplegia with nystagmus and ataxia occurred repeatedly within several months after the discontinuation of 100 mg of thiamine per day. There were no extrapyramidal features.
For discussion of the glu320-to-gln (E320Q) mutation in the SLC19A3 gene that was found in compound heterozygous state in 2 Japanese brothers with biotin-thiamine-responsive basal ganglia disease (BTBGD; 607483) by Kono et al. (2009), see 606152.0003.
In a Portuguese brother and sister with biotin-thiamine-responsive basal ganglia disease (BTBGD; 607483) Debs et al. (2010) identified compound heterozygosity for 2 mutations in the SLC19A3 gene: a 1-bp duplication (74dupT) in exon 2, resulting in a frameshift and premature termination, and an A-to-G transition in intron 3 (980-14A-G; 606152.0006), resulting in the skipping of exon 4 and an aberrantly spliced transcript degraded by nonsense-mediated mRNA decay. Each unaffected parent was heterozygous for 1 of the mutations. The brother was treated with high-dose biotin, which resulted in improvement of clinical features and disappearance of signal abnormalities on follow-up MRI. The sister was treated with high-dose biotin after worsening of her epilepsy, but she did not show improvement until thiamine was added.
For discussion of the splice site mutation in the SLC19A3 gene (980-14A-G) that was found in compound heterozygous state in sibs with biotin-thiamine-responsive basal ganglia disease (BTBGD; 607483) by Debs et al. (2010), see 606152.0005.
In 9 patients from 3 unrelated Moroccan families with biotin-thiamine-responsive basal ganglia disease (BTBGD; 607483), presenting as Leigh syndrome, Gerards et al. (2013) identified a homozygous c.20C-A transversion in the SLC19A3 gene, resulting in a ser7-to-ter (S7X) substitution. The mutation in the first family was found by a combination of homozygosity mapping and whole-exome sequencing, confirmed by Sanger sequencing, and filtered against the dbSNP (build 132) and 1000 Genomes Project databases. The mutation, which segregated with the disorder in the family, was not present in 460 control alleles. The mutations in the other 2 Moroccan families were found by direct sequencing of the SLC19A3 gene in 17 patients with Leigh syndrome. Haplotype analysis indicated a founder effect estimated to have occurred 1,250 to 1,750 years ago. The families all came from the Al Hoceima region in northern Morocco; 2 of the families were consanguineous. In vitro functional expression studies showed that the S7X mutant protein had no thiamine transporter activity, consistent with a complete loss of function.
Debs, R., Depienne, C., Rastetter, A., Bellanger, A., Degos, B., Galanaud, D., Keren, B., Lyon-Caen, O., Brice, A., Sedel, F. Biotin-responsive basal ganglia disease in ethnic Europeans with novel SLC19A3 mutations. Arch. Neurol. 67: 126-130, 2010. [PubMed: 20065143] [Full Text: https://doi.org/10.1001/archneurol.2009.293]
Eichler, F. S., Swoboda, K. J., Hunt, A. L., Cestari, D. M., Rapalino, O. Case 38-2017: A 20-year-old woman with seizures and progressive dystonia. New Eng. J. Med. 377: 2376-2384, 2017. [PubMed: 29236641] [Full Text: https://doi.org/10.1056/NEJMcpc1706109]
Eudy, J. D., Spiegelstein, O., Barber, R. C., Wlodarczyk, B. J., Talbot, J., Finnell, R. H. Identification and characterization of the human and mouse SLC19A3 gene: a novel member of the reduced folate family of micronutrient transporter genes. Molec. Genet. Metab. 71: 581-590, 2000. [PubMed: 11136550] [Full Text: https://doi.org/10.1006/mgme.2000.3112]
Gerards, M., Kamps, R., van Oevelen, J., Boesten, I., Jongen, E., de Koning, B., Scholte, H. R., de Angst, I., Schoonderwoerd, K., Sefiani, A., Ratbi, I., Coppieters, W., Karim, L., de Coo, R., van den Bosch, B., Smeets, H. Exome sequencing reveals a novel Moroccan founder mutation in SLC19A3 as a new cause of early-childhood fatal Leigh syndrome. Brain 136: 882-890, 2013. [PubMed: 23423671] [Full Text: https://doi.org/10.1093/brain/awt013]
Kono, S., Miyajima, H., Yoshida, K., Togawa, A., Shirakawa, K., Suzuki, H. Mutations in a thiamine-transporter gene and Wernicke's-like encephalopathy. (Letter) New. Eng. J. Med. 360: 1792-1794, 2009. [PubMed: 19387023] [Full Text: https://doi.org/10.1056/NEJMc0809100]
Rajgopal, A., Edmondnson, A., Goldman, I. D., Zhao, R. SLC19A3 encodes a second thiamine transporter ThTr2. Biochim. Biophys. Acta 1537: 175-178, 2001. [PubMed: 11731220] [Full Text: https://doi.org/10.1016/s0925-4439(01)00073-4]
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]
Subramanian, V. S., Marchant, J. S., Said, H. M. Biotin-responsive basal ganglia disease-linked mutations inhibit thiamine transport via hTHTR2: biotin is not a substrate for hTHTR2. Am. J. Physiol. Cell Physiol. 291: C851-C859, 2006. [PubMed: 16790503] [Full Text: https://doi.org/10.1152/ajpcell.00105.2006]
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]
Vernau, K. M., Runstadler, J. A., Brown, E. A., Cameron, J. M., Huson, H. J., Higgins, R. J., Ackerley, C., Sturges, B. K., Dickinson, P. J., Puschner, B., Giulivi, C., Shelton, G. D., Robinson, B. H., DiMauro, S., Bollen, A. W., Bannasch, D. L. Genome-wide association analysis identifies a mutation in the thiamine transporter 2 (SLC19A3) gene associated with Alaskan Husky encephalopathy. PLoS One 8: e57195, 2013. Note: Electronic Article. [PubMed: 23469184] [Full Text: https://doi.org/10.1371/journal.pone.0057195]
Vernau, K., Napoli, E., Wong, S., Ross-Inta, C., Cameron, J., Bannasch, D., Bollen, A., Dickinson, P., Giulivi, C. Thiamine deficiency-mediated brain mitochondrial pathology in Alaskan Huskies with mutation in SLC19A3.1. Brain Path. 25: 441-453, 2015. [PubMed: 25117056] [Full Text: https://doi.org/10.1111/bpa.12188]
Zeng, W.-Q., Al-Yamani, E., Acierno, J. S., Jr., Slaugenhaupt, S., Gillis, T., MacDonald, M. E., Ozand, P. T., Gusella, J. F. Biotin-responsive basal ganglia disease maps to 2q36.3 and is due to mutations in SLC19A3. Am. J. Hum. Genet. 77: 16-26, 2005. [PubMed: 15871139] [Full Text: https://doi.org/10.1086/431216]