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SLC19A3 (solute carrier family 19 (thiamine transporter), member 3)

Identity

Other namesBBGD
THMD2
THTR2
HGNC (Hugo) SLC19A3
LocusID (NCBI) 80704
Location 2q36.3
Location_base_pair Starts at 228549926 and ends at 228582745 bp from pter ( according to hg19-Feb_2009)  [Mapping]
Local_order According to the NCBI Homo sapiens Annotation Release 106, SLC19A3 is flanked by genes including: ArfGAP with FG repeats 1 (AGFG1), microRNA 5703 (MIR5703), chromosome 2 open reading frame 83 (C2orf83), 5S ribosomal pseudogene 121 (RNA5SP121), and small nuclear ribonucleoprotein polypeptide G pseudogene 8 (SNRPGP8).
 
  Genes flanking SLC19A3 on chromosome 2q37. The red box indicates the position and orientation of SLC19A3.

DNA/RNA

 
  The exon/intron structure of SLC19A3 gene (green) and its transcript variants (blue). The coding sequences and untranslated regions are indicated by filled and empty boxes, respectively.
Description The human SLC19A3 gene spans 32.9 kb of genomic DNA and is comprised of 8 exons. Orthologs of SLC19A3 are found in 47 different organisms.
Transcription 5 transcript variants for SLC19A3 are described from the NCBI Homo sapiens Annotation Release 106. NM_025243 (GenBank accession #) represents the main transcript (6 exons, 3775 bp) that encodes a peptide of 496 amino acids (Thiamine transporter-2, THTR-2). The remaining 4 variants were identified from computational annotation and include XM_005246871 (3836 bp, 6 exons, 546 aa), XM_005246874 (3288 bp, 7 exons, 492 aa), XM_006712779 (3210 bp, 6 exons, 501 aa) and XM_005246875 (1257 bp, 4 exons, 383 aa).
The stimulating protein-1 (SP1)/ guanosine cytidine (GC) box has been identified in the thiamine-responsive region of SLC19A3 promoter, and SP1 transcriptional factor was reported for regulating THTR-2 expression in response to extracellular thiamine level (Nabokina et al., 2013).
Pseudogene Two SLC19A3-related pseudogenes have been reported, namely LOC100130121 locating at chromosome 7p11, and LOC100420667 locating at chromosome 2q37.

Protein

Note The protein product of SLC19A3 gene is often referred as thiamine transporter-2 (THTR-2).
Description A thiamine transporter protein of 496 amino acid residues, 56 kDa, containing 12 transmembrane domains, and cytosolic N- and C-terminals (Eudy et al., 2000).
Expression SLC19A3 expression has been widely detetced in human tissues including brain, heart, gastrointestinal tract, lung, pancreas, muscle, ovary, testis, adrenal gland, with the highest levels observed in placenta, liver and kidney (Eudy et al., 2000). A more restricted pattern of SLC19A3 expression was found in mouse tissues, including only brain, heart, lung, kidney and small intestine.
Localisation Plasma membrane. In polarized intestinal epithelial cells, THTR-2 are restrictedly localized at the apical membrane domain (Subramanian et al., 2006a).
Function THTR-2 mediates the transmembrane uptake of thiamine (vitamin B1) via a proton anti-port mechanism (Rajgopal et al., 2001). This thiamine uptake process was reported to be temperature-, energy- and pH-dependent (Ashokkumar et al., 2006; Subramanian et al., 2007), and is adaptively regulated by the extracellular thiamine level through transcriptional regulation of the SLC19A3 gene (Nabokina et al., 2013). In human intestinal epithelial cells, THTR-2 interacts with the human transmembrane 4 super-family 4 (TM4SF4) and influences the intestinal thiamine uptake (Subramanian et al., 2014).
Homology THTR-2 protein belongs to the SLC19 gene family (folate/thiamine transporter family) of solute carriers. Two other members of the family are SLC19A1 (a folate transporter) and SLC19A2 (a thiamine transporter, THTR-1), which share 42% and 53% amino acid sequence identities to the human THTR-2 (Ganapathy et al., 2004). The human SLC19A3 gene is conserved in chimpanzee, Rhesus monkey, dog, cow, mouse, rat, chicken, zebrafish, fruit fly, and mosquito.

Mutations

Germinal Mutations in SLC19A3 (homozygous and compound heterozygous) have been associated with different neurological disorders, including biotin responsive basal ganglia disease (BBGD), Wernicke's-like encephalopathy, and Leigh syndrome. The pathogenic mutations identified to date include p.Gly23Val, p.Thr422Ala (Zeng et al., 2005), p.Lys44Glu, p.Glu320Gln (Kono et al., 2009; Yamada et al., 2010), c.74dupT, IVS3-14A>G (Debs et al., 2010), p.Ser7* (Gerards et al., 2013), p.Gln393*, p.Ser181Pro, p.Leu385Arg, p.Tyr169*, p.Ser176Tyr, p.Val299fs and p.Ser444Arg (Kevelam et al., 2013).

Implicated in

Entity Breast cancer
Note SLC19A3 expression was downregulated in breast cancer tumors as compared to the normal tissues (Ng et al., 2011). Exogenous expression of SLC19A3 in breast cancer cells resulted in an increased sensitivity to doxorubicin- and radiation-induced apoptosis (Liu et al., 2003), and modulated the gene expression associated with prostaglandin metabolism (Liu et al., 2004).
  
Entity Gastric cancer
Note Hypermethylation of SLC19A3 promoter was detected in gastric cancer cell lines and carcinoma tissues, which led to the epigenetic downregulation of SLC19A3 expression (Liu et al., 2009). The methylation status of SLC19A3 promoter was further validated in plasma samples of breast and gastric cancer patients, suggesting it as a potential blood biomarker for cancer diagnosis (Ng et al., 2011).
  
Entity Biotin-responsive basal ganglia disease
Note Biotin-responsive basal ganglia disease (BBGD) is a recessive metabolic disorder caused by the homozygous or compound heterozygous mutations in SLC19A3 (Zeng et al., 2005; Debs et al., 2010). Functional study of SLC19A3 [p.Gly23Val and p.Thr422Ala] mutants demonstrated that these 2 mutations did not affect THTR-2 protein trafficking to the apical membrane, but resulting in impaired thiamine transport activity (Subramanian et al., 2006b).
  
Entity Leigh syndrome
Note Mutational dysfunction of SLC19A3 has been reported to be associated with Leigh syndrome. A nonsense mutation (c.20C>A; p.Ser7*) has been detected in SLC19A3, and was described as a founder mutation in the Moroccan population (Gerards et al., 2013).
  
Entity Wernicke's-like encephalopathy
Note Compound mutations in SLC19A3 [p.Lys44Glu and p.Glu320Gln] were reported in patients with Wernicke's-like encephalopathy. From the expression study, p.Lys44Glu mutantion resulted in impaired THTR-2 intracellular transport, whereas the p.Glu320Gln mutant showed normal cell surface localization but a significiantly decreased thiamine uptake activity (Kono et al., 2009).
  
Entity Apoptosis
Note THTR2-transfected breast cancer cells were found an increase in sensitivity to chemotherapy agent doxorubicin and ionizing radiation, and an increase in apoptosis involving the caspase-3-dependent pathway (Liu et al., 2003).
  
Entity Diabetic nephropathy
Note SLC19A3 expression was demonstrated to be down-regulated in kidney proximal tubular epithelium under high glucose concentration, which led to the impaired renal re-uptake of thiamine, and producing thiamine insufficiency. This implies a novel mechanism of renal thiamine mishandling linked to the development of diabetic nephropathy (Larkin et al., 2012).
  
Entity Biotin deficiency
Note SLC19A3 expression was found to be strikingly repressed in human leukocytes upon marginal biotin deficiency, suggesting it as a potential indicator of biotin status (Vlasova et al., 2005).
  

External links

Nomenclature
HGNC (Hugo)SLC19A3   16266
Cards
AtlasSLC19A3ID45635ch2q36
Entrez_Gene (NCBI)SLC19A3  80704  solute carrier family 19 (thiamine transporter), member 3
GeneCards (Weizmann)SLC19A3
Ensembl (Hinxton)ENSG00000135917 [Gene_View]  chr2:228549926-228582745 [Contig_View]  SLC19A3 [Vega]
ICGC DataPortalENSG00000135917
AceView (NCBI)SLC19A3
Genatlas (Paris)SLC19A3
WikiGenes80704
SOURCE (Princeton)NM_025243
Genomic and cartography
GoldenPath (UCSC)SLC19A3  -  2q36.3   chr2:228549926-228582745 -  2q37   [Description]    (hg19-Feb_2009)
EnsemblSLC19A3 - 2q37 [CytoView]
Mapping of homologs : NCBISLC19A3 [Mapview]
OMIM606152   607483   
Gene and transcription
Genbank (Entrez)AF271633 AF283317 AI056985 AK301490 AK312464
RefSeq transcript (Entrez)NM_025243
RefSeq genomic (Entrez)AC_000134 NC_000002 NC_018913 NG_016359 NT_005403 NW_001838866 NW_004929305
Consensus coding sequences : CCDS (NCBI)SLC19A3
Cluster EST : UnigeneHs.221597 [ NCBI ]
CGAP (NCI)Hs.221597
Alternative Splicing : Fast-db (Paris)GSHG0018391
Alternative Splicing GalleryENSG00000135917
Gene ExpressionSLC19A3 [ NCBI-GEO ]     SLC19A3 [ SEEK ]   SLC19A3 [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ9BZV2 (Uniprot)
NextProtQ9BZV2  [Medical]
With graphics : InterProQ9BZV2
Splice isoforms : SwissVarQ9BZV2 (Swissvar)
Domains : Interpro (EBI)Folate_carrier    MFS_dom_general_subst_transpt    ThTr-2   
Related proteins : CluSTrQ9BZV2
Domain families : Pfam (Sanger)Folate_carrier (PF01770)   
Domain families : Pfam (NCBI)pfam01770   
DMDM Disease mutations80704
Blocks (Seattle)Q9BZV2
Human Protein AtlasENSG00000135917
Peptide AtlasQ9BZV2
HPRD07311
IPIIPI00019278   IPI00922230   IPI00917723   IPI00917280   IPI00917432   IPI00916963   IPI00917761   
Protein Interaction databases
DIP (DOE-UCLA)Q9BZV2
IntAct (EBI)Q9BZV2
FunCoupENSG00000135917
BioGRIDSLC19A3
IntegromeDBSLC19A3
STRING (EMBL)SLC19A3
Ontologies - Pathways
QuickGOQ9BZV2
Ontology : AmiGOplasma membrane  vitamin metabolic process  water-soluble vitamin metabolic process  thiamine uptake transmembrane transporter activity  integral component of membrane  thiamine-containing compound metabolic process  small molecule metabolic process  thiamine transmembrane transport  thiamine transmembrane transport  
Ontology : EGO-EBIplasma membrane  vitamin metabolic process  water-soluble vitamin metabolic process  thiamine uptake transmembrane transporter activity  integral component of membrane  thiamine-containing compound metabolic process  small molecule metabolic process  thiamine transmembrane transport  thiamine transmembrane transport  
Pathways : KEGGVitamin digestion and absorption   
REACTOMEQ9BZV2 [protein]
REACTOME PathwaysREACT_116125 Disease [pathway]
REACTOME PathwaysREACT_111217 Metabolism [pathway]
Protein Interaction DatabaseSLC19A3
Wikipedia pathwaysSLC19A3
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)SLC19A3
SNP (GeneSNP Utah)SLC19A3
SNP : HGBaseSLC19A3
Genetic variants : HAPMAPSLC19A3
1000_GenomesSLC19A3 
ICGC programENSG00000135917 
CONAN: Copy Number AnalysisSLC19A3 
Somatic Mutations in Cancer : COSMICSLC19A3 
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
LOVD (Leiden Open Variation Database)MSeqDR-LSDB Mitochondrial Disease Locus Specific Database
DECIPHER (Syndromes)2:228549926-228582745
Mutations and Diseases : HGMDSLC19A3
OMIM606152    607483   
MedgenSLC19A3
GENETestsSLC19A3
Disease Genetic AssociationSLC19A3
Huge Navigator SLC19A3 [HugePedia]  SLC19A3 [HugeCancerGEM]
Genomic VariantsSLC19A3  SLC19A3 [DGVbeta]
Exome VariantSLC19A3
dbVarSLC19A3
ClinVarSLC19A3
snp3D : Map Gene to Disease80704
DGIdb (Curated mutations)SLC19A3
DGIdb (Drug Gene Interaction db)SLC19A3
General knowledge
Homologs : HomoloGeneSLC19A3
Homology/Alignments : Family Browser (UCSC)SLC19A3
Phylogenetic Trees/Animal Genes : TreeFamSLC19A3
Chemical/Protein Interactions : CTD80704
Chemical/Pharm GKB GenePA38397
Clinical trialSLC19A3
Cancer Resource (Charite)ENSG00000135917
Other databases
Probes
Litterature
PubMed32 Pubmed reference(s) in Entrez
CoreMineSLC19A3
GoPubMedSLC19A3
iHOPSLC19A3

Bibliography

Identification and characterization of the human and mouse SLC19A3 gene: a novel member of the reduced folate family of micronutrient transporter genes.
Eudy JD, Spiegelstein O, Barber RC, Wlodarczyk BJ, Talbot J, Finnell RH.
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SLC19A3 encodes a second thiamine transporter ThTr2.
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PMID 11731220
 
Down-regulation of thiamine transporter THTR2 gene expression in breast cancer and its association with resistance to apoptosis.
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Mol Cancer Res. 2003 Jul;1(9):665-73.
PMID 12861052
 
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Ganapathy V, Smith SB, Prasad PD.
Pflugers Arch. 2004 Feb;447(5):641-6. Epub 2003 May 6. (REVIEW)
PMID 14770311
 
Thiamine transporter gene expression and exogenous thiamine modulate the expression of genes involved in drug and prostaglandin metabolism in breast cancer cells.
Liu S, Stromberg A, Tai HH, Moscow JA.
Mol Cancer Res. 2004 Aug;2(8):477-87.
PMID 15328374
 
Biotin deficiency reduces expression of SLC19A3, a potential biotin transporter, in leukocytes from human blood.
Vlasova TI, Stratton SL, Wells AM, Mock NI, Mock DM.
J Nutr. 2005 Jan;135(1):42-7.
PMID 15623830
 
Biotin-responsive basal ganglia disease maps to 2q36.3 and is due to mutations in SLC19A3.
Zeng WQ, Al-Yamani E, Acierno JS Jr, Slaugenhaupt S, Gillis T, MacDonald ME, Ozand PT, Gusella JF.
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PMID 15871139
 
Thiamin uptake by the human-derived renal epithelial (HEK-293) cells: cellular and molecular mechanisms.
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PMID 16705148
 
Targeting and trafficking of the human thiamine transporter-2 in epithelial cells.
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PMID 16371350
 
Biotin-responsive basal ganglia disease-linked mutations inhibit thiamine transport via hTHTR2: biotin is not a substrate for hTHTR2.
Subramanian VS, Marchant JS, Said HM.
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PMID 16790503
 
Vitamin B1 (thiamine) uptake by human retinal pigment epithelial (ARPE-19) cells: mechanism and regulation.
Subramanian VS, Mohammed ZM, Molina A, Marchant JS, Vaziri ND, Said HM.
J Physiol. 2007 Jul 1;582(Pt 1):73-85. Epub 2007 Apr 26.
PMID 17463047
 
Mutations in a thiamine-transporter gene and Wernicke's-like encephalopathy.
Kono S, Miyajima H, Yoshida K, Togawa A, Shirakawa K, Suzuki H.
N Engl J Med. 2009 Apr 23;360(17):1792-4. doi: 10.1056/NEJMc0809100.
PMID 19387023
 
Promoter hypermethylation mediates downregulation of thiamine receptor SLC19A3 in gastric cancer.
Liu X, Lam EK, Wang X, Zhang J, Cheng YY, Lam YW, Ng EK, Yu J, Chan FK, Jin H, Sung JJ.
Tumour Biol. 2009;30(5-6):242-8. doi: 10.1159/000243767. Epub 2009 Oct 7.
PMID 19816091
 
Biotin-responsive basal ganglia disease in ethnic Europeans with novel SLC19A3 mutations.
Debs R, Depienne C, Rastetter A, Bellanger A, Degos B, Galanaud D, Keren B, Lyon-Caen O, Brice A, Sedel F.
Arch Neurol. 2010 Jan;67(1):126-30. doi: 10.1001/archneurol.2009.293.
PMID 20065143
 
A wide spectrum of clinical and brain MRI findings in patients with SLC19A3 mutations.
Yamada K, Miura K, Hara K, Suzuki M, Nakanishi K, Kumagai T, Ishihara N, Yamada Y, Kuwano R, Tsuji S, Wakamatsu N.
BMC Med Genet. 2010 Dec 22;11:171. doi: 10.1186/1471-2350-11-171.
PMID 21176162
 
Quantitative analysis and diagnostic significance of methylated SLC19A3 DNA in the plasma of breast and gastric cancer patients.
Ng EK, Leung CP, Shin VY, Wong CL, Ma ES, Jin HC, Chu KM, Kwong A.
PLoS One. 2011;6(7):e22233. doi: 10.1371/journal.pone.0022233. Epub 2011 Jul 18.
PMID 21789241
 
Glucose-induced down regulation of thiamine transporters in the kidney proximal tubular epithelium produces thiamine insufficiency in diabetes.
Larkin JR, Zhang F, Godfrey L, Molostvov G, Zehnder D, Rabbani N, Thornalley PJ.
PLoS One. 2012;7(12):e53175. doi: 10.1371/journal.pone.0053175. Epub 2012 Dec 28.
PMID 23285265
 
Exome sequencing reveals a novel Moroccan founder mutation in SLC19A3 as a new cause of early-childhood fatal Leigh syndrome.
Gerards M, Kamps R, van Oevelen J, Boesten I, Jongen E, de Koning B, Scholte HR, de Angst I, Schoonderwoerd K, Sefiani A, Ratbi I, Coppieters W, Karim L, de Coo R, van den Bosch B, Smeets H.
Brain. 2013 Mar;136(Pt 3):882-90. doi: 10.1093/brain/awt013. Epub 2013 Feb 18.
PMID 23423671
 
Exome sequencing reveals mutated SLC19A3 in patients with an early-infantile, lethal encephalopathy.
Kevelam SH, Bugiani M, Salomons GS, Feigenbaum A, Blaser S, Prasad C, Haberle J, Baric I, Bakker IM, Postma NL, Kanhai WA, Wolf NI, Abbink TE, Waisfisz Q, Heutink P, van der Knaap MS.
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PMID 23482991
 
Adaptive regulation of human intestinal thiamine uptake by extracellular substrate level: a role for THTR-2 transcriptional regulation.
Nabokina SM, Subramanian VS, Valle JE, Said HM.
Am J Physiol Gastrointest Liver Physiol. 2013 Oct 15;305(8):G593-9. doi: 10.1152/ajpgi.00237.2013. Epub 2013 Aug 29.
PMID 23989004
 
Association of TM4SF4 with the human thiamine transporter-2 in intestinal epithelial cells.
Subramanian VS, Nabokina SM, Said HM.
Dig Dis Sci. 2014 Mar;59(3):583-90. doi: 10.1007/s10620-013-2952-y. Epub 2013 Nov 27.
PMID 24282057
 
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Contributor(s)

Written08-2014Ava Kwong, Vivian Y Shin, John C W Ho
Department of Surgery, The University of Hong Kong, Hong Kong, China

Citation

This paper should be referenced as such :
Kwong A, Shin VY, Ho JCW
SLC19A3 (solute carrier family 19 (thiamine transporter), member 3);
Atlas Genet Cytogenet Oncol Haematol. August 2014
Free online version   Free pdf version   [Bibliographic record ]
URL : http://AtlasGeneticsOncology.org/Genes/SLC19A3ID45635ch2q36.html

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indexed on : Thu Dec 4 15:06:37 CET 2014

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