Thiamine Transporter Gene Research Articles

Clinical profile and thiamine transporter gene (SLC19A2 and SLC19A3) variations in infants with thiamine-responsive pulmonary hypertension and acute respiratory infection

Abstract Maternal thiamine deficiency is prevalent in low- and middle-income countries. Thiamine-responsive pulmonary hypertension (TRPHTN) in exclusively breastfed infants is reported in India. Thiamine transporter gene (ThTR) variations have not been studied. This study compared the presentation of exclusively breastfed infants with respiratory distress diagnosed as TRPHTN or acute respiratory infection (ARI). We investigated pathogenic variations in the SLC19A2 and SLC19A3 ThTr genes in a representative sample. Observational study. Tertiary care pediatric unit of a teaching hospital in southern India. Data collection was prospective. We included exclusively breastfed infants between 1 and 6 months of age with respiratory distress. Infants with PHTN in echocardiography and lactic acidosis (LA) received thiamine. TRPHTN was diagnosed based on response within 72 h. Infants with fever, chest findings, and positive microbiology were managed as ARI. The ThTr genes were sequenced and analyzed. Chi-square and stratified analysis were done to determine TRPHTN risk. Forty infants with TRPHTN and 42 with ARI were included. The median pulmonary arterial pressure in the TRPHTN group was 51.5 mmHg. Mild PHTN was seen in 65%, moderate in 22.5%, and severe in 12.5%. Cardiac failure (P < .001), stridor and aphonia (P < .001), encephalopathy (P = .024), LA (P < .001), and PHTN (P <.001) facilitated the diagnosis. The adjusted risk was 17.3 (95% confidence interval 7.8–38.3; P <.001). The ThTR sequencing showed wild-type genotypes. TRPHTN has a distinct, identifiable presentation. Lactate and pulmonary pressure estimations are useful investigations in thiamine deficiency endemic areas. We could not demonstrate a genetic variation that determines susceptibility.

Acute Encephalopathy Caused by Inherited Metabolic Diseases.

Acute encephalopathy is a critical medical condition that typically affects previously healthy children and young adults and often results in death or severe neurological sequelae. Inherited metabolic diseases that can cause acute encephalopathy include urea cycle disorders, amino acid metabolism disorders, organic acid metabolism disorders, fatty acid metabolism disorders, mutations in the thiamine-transporter gene, and mitochondrial diseases. Although each inherited metabolic disease is rare, its overall incidence is reported as 1 in 800-2500 patients. This narrative review presents the common inherited metabolic diseases that cause acute encephalopathy. Since diagnosing inherited metabolic diseases requires specific testing, early metabolic/metanolic screening tests are required when an inherited metabolic disease is suspected. We also describe the symptoms and history associated with suspected inherited metabolic diseases, the various tests that should be conducted in case of suspicion, and treatment according to the disease group. Recent advancements made in the understanding of some of the inherited metabolic diseases that cause acute encephalopathy are also highlighted. Acute encephalopathy due to inherited metabolic diseases can have numerous different causes, and recognition of the possibility of an inherited metabolic disease as early as possible, obtaining appropriate specimens, and proceeding with testing and treatment in parallel are crucial in the management of these diseases.

Dietary thiamine modulates carbohydrate metabolism, antioxidant status, and alleviates hypoxia stress in oriental river prawn Macrobrachium nipponense (de Haan)

Hypoxia is one of the challenges in prawns aquaculture. However, the role of thiamine, which is a coenzyme in carbohydrate metabolism with antioxidant properties, in reducing hypoxia in prawns aquaculture is currently unknown. We investigated the effects of thiamine on antioxidant status, carbohydrate metabolism and acute hypoxia in oriental river prawn, Macrobrachium nipponense. One thousand eight hundred prawns (0.123 ± 0.003 g) were fed five diets (60 prawns each tank, six replicates per diet) supplemented with graded thiamine levels (5.69, 70.70, 133.67, 268.33 and 532.00 mg/kg dry mater) for eight weeks and then exposed to hypoxia stress for 12 h followed by reoxyegnation for 12 h. The results showed that, under normoxia, prawns fed the 133.67 or 268.33 mg/kg thiamine diet had significantly lower glucose 6-phosphatedehydrogenase, succinate dehydrogenase and phosphoenolpyruvate carboxykinase activities than those fed the other diets. Moreover, total antioxidant capacity (T-AOC) increased significantly when prawns were fed the 133.67 mg/kg thiamine diet. Superoxide dismutase (SOD) activity and malonaldehyde (MDA) content also increased significantly when prawns were fed the 268.33 or 532.00 mg/kg thiamine diet under hypoxia. And the significantly increased SOD activity and MDA level also observed in prawns fed 532.00 mg/kg thiamine under reoxygenation. Under normoxia, prawns fed the 70.70 or 133.67 mg/kg thiamine diet decreased the mRNA expressions of AMP-activated protein kinase-alpha (AMPK-α), pyruvate dehydrogenase-E1-α subunit (PDH-E1-α) and hypoxia-inducible factor-1s (HIF-1α, HIF-1β), but increased the mRNA expressions of phosphofructokinase (PFK) significantly. After 12 h of hypoxia, the energy metabolism related genes (AMPK-β, AMPK-γ, PFK, PDH-E1-α), hypoxia-inducible factor related genes (HIF-1α, HIF-1β) and thiamine transporter gene (SLC19A2) were up-regulated significantly in prawns fed the 133.67 or 268.33 mg/kg thiamine diets. After 12 h of reoxygenation, prawns fed the 133.67 or 268.33 mg/kg diet significantly decreased the SOD activity, MDA level and SLC19A2 mRNA expression compared with other diets. The optimum thiamine was 161.20 mg/kg for minimum MDA content and 143.17 mg/kg for maximum T-AOC activity based on cubic regression analysis. In summary, supplementing 143.17 to 161.20 mg/kg thiamine in the diets for M. nipponense improves the antioxidant capacity under normoxia and reduces the oxidative damage under hypoxia stress.

Gayet wernicke encephalopathy: Don’t miss this neuropsychiatric emergency!

IntroductionGayet Wernicke Encephalopathy (GWE) is a diagnostic and therapeutic neuropsychiatric emergency due to thiamin deficiency (vitamin B1).ObjectivesThe purpose of our work is to recall some clinical situations suspecting GWE, along with radiological and evolutionary profile.MethodsWe conducted a retrospective study concerning patients who were hospitalized in the neurology department of Habib Bourguiba Hospital between 2013 and 2020 for management of GWE.ResultsThe median age of 7 patients was 39.57 years with sex ratio (H/F):1.33. The most common risk factor found is incoercible vomiting (5 patients), followed by chronic alcoholism (3 patients). Confusional state was the most frequent symptom found in 4 patients. The characteristic clinical triad of confusion, oculomotor disorders and ataxia was only found in 2 patients. Neuroimaging showed a typical aspect in 3 patients. The serum levels of thiamine were low in five patients and normal in two patients. After receiving parental than oral thiamin supplementation, three patients were independent after one month with a mRS score <3.ConclusionsGWE is an acute neuropsychiatric emergency. Chronic alcoholism is recognized as its most common cause. The clinical triad is not constantly present. MRI shows typically bilateral symmetrical hyperintensities in periaqueductal area, periventricular region, thalami and mammillary bodies. Thiamin level can be normal since it does not accurately represent body thiamine status or in case of mutations in a thiamine-transporter gene. Thiamine therapy is warranted if any component of the GWE triad is present in an appropriate clinical setting to prevent irreversible neurological sequelae.

Identification of a novel pyrithiamine resistance marker gene thiI for genome co-editing in Aspergillus oryzae

Marker genes are essential for gene modification and genome editing of microorganisms. In Aspergillus oryzae, a widely used host for enzyme production, only a few marker genes can be used for positive selection. One of these genes, the pyrithiamine (PT) resistance marker gene thiA, is not useful for CRISPR/Cas9 genome editing because of its unique resistance-conferring mechanism. In this study, a novel PT resistance marker was investigated considering its potential applications in genome editing. A mutant resistant to PT was selected from UV-mutagenized A. oryzae RIB40. Whole genome analysis was conducted on the mutants, and a novel candidate gene for PT resistance was identified. This candidate gene exhibited similarity to the thiamine transporter gene thi9 of Schizosaccharomyces pombe and was designated as thiI. A thiI loss-of-function mutant was generated using the CRISPR/Cas9 genome editing system to investigate its effect on PT resistance. This mutant showed PT resistance and exhibited no growth defect or auxotrophy. The thiI gene was further investigated for its use as a selection marker in genome co-editing. Ribonucleoprotein complex comprising recombinant Cas9 nuclease and sgRNA targeting thiI or another target gene (wA or sreA) was prepared and simultaneously introduced into A.oryzae RIB40. thiI and target gene double loss-of-function mutants were efficiently selected on PT-containing medium. thiI was shown to be a useful marker gene in A.oryzae for use in genome editing. This study is expected to provide insights, which will promote basic research and industrial applications of A.oryzae.

Neuropathological characteristics of the brain in two patients with SLC19A3 mutations related to the biotin-thiamine-responsive basal ganglia disease.

<i>Biotin-thiamine-responsive basal ganglia disease is a severe form of a rare neurogenetic disorder caused by pathogenic molecular variants in the thiamine transporter gene. Nowadays, a potentially effective treatment is known, therefore the early diagnosis is mandatory. The aim of the paper was to assess the contribution of neuropathological and magnetic resonance imaging (MRI) studies to a proper diagnosis. We present the brain study of two Polish patients with SLC19A3 mutations, including (1) an infant with an intriguing "walnut" appearance of the brain autopsied many years before the discovery of the SLC19A3 defect, and (2) a one-year-old patient with clinical features of Leigh syndrome. In patient 2, biotin/thiamine responsiveness was not tested at the time of diagnosis and causal treatment started with one-year delay. The central nervous system lesions found in the patients displayed almost clearly a specific pattern for SLC19A3 defect, as previously proposed in diagnostic criteria. Our study presents a detailed description of neuropathological and MRI findings of both patients. We confirm that the autopsy and/or MRI of the brain is sufficient to qualify a patient with an unknown neuropathological disorder directly for SLC19A3 mutations testing and a prompt trial of specific treatment. </i>.

Novel Mutation in the SLC19A2 Gene in an Iranian Family with Thiamine-Responsive Megaloblastic Anemia: A Series of Three Cases

Thiamine-responsive megaloblastic anemia (TRMA) is a clinical triad characterized by megaloblastic anemia, non-autoimmune diabetes mellitus, and sensory-neural hearing loss. Mutations in the thiamine transporter gene, solute carrier family 19, member 2 (SLC19A2), have been associated with TRMA. Three pediatric patients from a large consanguineous Iranian family with hyperglycemia, anemia, and hearing loss were clinically diagnosed with TRMA. In all three patients, TRMA was confirmed by direct sequencing of the SLC19A2 gene that revealed a novel missense homozygous mutation c.382 G>A (p.E128K). This mutation results in the substitution of glutamic acid to lysine at position 128 in exon 2 and was not detected in 200 control chromosomes. Thiamine therapy reversed the anemia and alleviated the hyperglycemia in all three patients. We recommend sequence analysis of the SLC19A2 gene in individuals with a clinical triad of diabetes mellitus, hearing loss, and anemia. The administration of thiamine ameliorates the megaloblastic anemia and the hyperglycemia in patients with TRMA.Conflict of interest:None declared.

Low-Thiamine Diet Increases Mammary Tumor Latency in FVB/N-Tg(MMTVneu) Mice

We have previously described the down-regulation of thiamine transporter gene expression in breast cancer, and others have shown an epidemiologic relationship between obesity and breast cancer. To further explore the relationship of thiamine, fat, and breast cancer, we exposed FVB/N-Tg(MMTVneu)202Mul/J female mice to four diets that varied in fat and thiamine content (15 mice per group). The high-fat (HF) diet contained 60 % of calories from fat and the normal-fat (NF) diet contained 10 % of calories from fat. The normal-thiamine (NT) diet contained 6 mg thiamine per 4057 kcal and the low-thiamine (LT) diet contained 2 mg thiamine/4057 kcal. Tumor latency was 203 days from date of birth for the HF/NT group, 210 days for the HF/LT group, 225 days for the NF/NT group, and 295 days for the NF/LT group (p = 0.01). The time to endpoint of a mammary tumor volume > 1000 mm3 was 231 days for the HF/NT group, 238 days for the HF/LT group, 257 days for the NF/NT group, and undefined (>310 days) for the NF/LT group (p < 0.001). The high-fat groups were heavier than the normal-fat groups, and the low-thiamine group had a lower serum thiamine level than the normal-thiamine group. There were no differences in the number of pulmonary metastases between groups. This study demonstrates a potential role for dietary thiamine, and an interaction between thiamine and fat, in breast cancer progression.

NOVEL MUTATION IN THE SLC19A2 GENE IN THIAMINE-RESPONSIVE MEGALOBLASTIC ANEMIA (ROGERS’ SYNDROME)

Introduction: The Thiamine Transporter gene SLC19A2 is the only gene known to be associated with TRMA. This syndrome is a trial clinical characterized by megaloblastic anemia, nonautoimmune diabetes mellitus and sensory-neural hearing loss. Methods: Described here are three children from consanguineous Iranian families with thiamine – responsive megaloblastic anemia (TRMA) or Rogers' syndrome. Case one and two were siblings of healthy first-cousin parents and case three from a healthy second-cousin couple. These cases presented with hyperglycemia, anemia, and hearing loss. Thiamine reversed the anemia and there was a satisfactory response for the hyperglycemia as well. Results: In all three patients, direct sequencing revealed a homozygous mutation c.38 G>A (P.E.128K) resulting in the substitution of glutamic acid to lysine at position 128 in exon 2 of the SLC19A2 gene on chromosome 1q23.3. This novel mutation was confirmed by the PCR RFLP assay of more than 100 control alleles. Conclusion: TRMA or Rogers' syndrome should be considered for patients with diabetes (DM) and other symptoms, including hearing loss and anemia. Early diagnosis can assist families in planning future pregnancies. The administration of thiamine ameliorates the megaloblastic anemic condition and produces a better response in DM.

Mutation in the thiamine transporter gene and Wernicke&apos;s like encephalopathy

Mutation in the thiamine transporter gene and Wernicke&apos;s like encephalopathy

3FC1.5 Biotin-responsive basal ganglia disease: New features in two Spanish siblings with mutations in the second thiamine transporter gene SLC19A3

3FC1.5 Biotin-responsive basal ganglia disease: New features in two Spanish siblings with mutations in the second thiamine transporter gene SLC19A3

Thiamine Prevents Obesity and Obesity-Associated Metabolic Disorders in OLETF Rats

We previously found that thiamine mitigates metabolic disorders in spontaneously hypertensive rats, harboring defects in glucose and fatty acid metabolism. Mutation of thiamine transporter gene SLC19A2 is linked to type 2 diabetes mellitus. The current study extends our hypothesis that thiamine intervention may impact metabolic abnormalities in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, exhibiting obesity and metabolic disorders similar to human metabolic syndrome. Male OLETF rats (4 wk old) were given free access to water containing either 0.2% or 0% of thiamine for 21 and 51 wk. At the end of treatment, blood parameters and cardiac functions were analyzed. After sacrifice, organs weights, histological findings, and hepatic pyruvate dehydrogenase (PDH) activity in the liver were evaluated. Thiamine intervention averted obesity and prevented metabolic disorders in OLETF rats which accompanied mitigation of reduced lipid oxidation and increased hepatic PDH activity. Histological evaluation revealed that thiamine alleviated adipocyte hypertrophy, steatosis in the liver, heart, and skeletal muscle, sinusoidal fibrosis with formation of basement membranes (called pseudocapillarization) which accompanied significantly reduced expression of laminin β1 and nidogen-1 mRNA, interstitial fibrosis in the heart and kidney, fatty degeneration in the pancreas, thickening of the basement membrane of the vasculature, and glomerulopathy and mononuclear cell infiltration in the kidney. Cardiac and renal functions were preserved in thiamine treatment. Thiamine has a potential to prevent obesity and metabolic disorders in OLETF rats.

Mutations in a Thiamine-Transporter Gene and Wernicke's-like Encephalopathy

To the Editor: We report on two previously healthy Japanese brothers with a newly discovered recessively inherited syndrome similar to Wernicke's encephalopathy that developed in the second decade ...

Both Thiamine Uptake and Biosynthesis of Thiamine Precursors Are Required for Intracellular Replication ofListeria monocytogenes

Thiamine pyrophosphate is an essential cofactor involved in central metabolism and amino acid biosynthesis and is derived from thiamine (vitamin B(1)). The extent to which this metabolite is available to bacterial pathogens replicating within host cells is still little understood. Growth studies using modified minimal Welshimer's broth (mMWB) supplemented with thiamine or the thiamine precursor hydroxymethylpyrimidine (HMP) showed that Listeria monocytogenes, in agreement with bioinformatic prediction, is able to synthesize thiamine only in the presence of HMP. This appears to be due to a lack of ThiC, which is involved in HMP synthesis. The knockout of thiD (lmo0317), which probably catalyzes the phosphorylation of HMP, inhibited growth in mMWB supplemented with HMP and reduced the replication rate of L. monocytogenes in epithelial cells. Mutation of a predicted thiamine transporter gene, lmo1429, led to reduced proliferation of L. monocytogenes in mMWB containing thiamine or thiamine phosphates and also within epithelial cells but had no influence on the expression of the virulence factors Hly and ActA. The toxic thiamine analogue pyrithiamine inhibited growth of wild-type strain EGD but not of the transporter mutant EGDDeltathiT. We also demonstrated that ThiT binds thiamine, a finding compatible with ThiT acting as the substrate-binding component of a multimeric thiamine transporter complex. These data provide experimental evidence that Lmo1429 homologs including Bacillus YuaJ are necessary for thiamine transport in gram-positive bacteria and are therefore proposed to be annotated "ThiT." Taken together, these data indicate that concurrent thiamine uptake and biosynthesis of thiamine precursors is a strategy of L. monocytogenes and possibly other facultative intracellular pathogens to enable proliferation within the cytoplasm.

Thiamine transporter mutation: an example of monogenic diabetes mellitus

Thiamine-responsive megaloblastic anemia (TRMA) is a rare syndrome characterized by diabetes mellitus (DM), anemia, and sensorineural deafness. We describe the clinical course and the molecular defect of a young woman who was diagnosed to have this syndrome. The patient is an 18-year-old girl who was born to non-consanguous parents. She was noted to be deaf-mute in the first year of life. She was diagnosed with DM at the age of 9 months and with severe anemia at the age of 2 years. An extensive work up could not identify the cause. She was treated with blood transfusions every 3-4 weeks for the past 16 years. A diagnosis of TRMA was suspected and the patient was treated with thiamine hydrochloride. Hemoglobin and platelets increased to normal values after a few weeks of thiamine therapy. Diabetic control significantly improved but she had no noticeable changes in the deafness. Peripheral blood DNA was extracted from the patient, her mother, aunt, and a healthy sister. Exons and exon-intron boundaries of the thiamine transporter gene SLC19A2 were PCR amplified and directly sequenced. A G515C homozygous mutation was identified in the SLC19A2 gene of the patient. This mutation changes Gly to Arg at codon 172 (G172R). The mother, an aunt, and a sister had a heterozygous G172R mutation. Mutations in thiamine transporter gene, SLC19A2, causes a rare form of monogenic diabetes, anemia, and sensorineural deafness. Thiamine induces a remarkable hematological response and improvement in the diabetic control but has no effect on deafness.

Direct genomic PCR sequencing of the high affinity thiamine transporter (SLC19A2) gene identifies three genetic variants in Wernicke Korsakoff syndrome (WKS)

Direct genomic PCR sequencing of the high affinity thiamine transporter (SLC19A2) gene identifies three genetic variants in Wernicke Korsakoff syndrome (WKS)

Thiamine Transporter Gene Expression and Exogenous Thiamine Modulate the Expression of Genes Involved in Drug and Prostaglandin Metabolism in Breast Cancer Cells

In previous studies, we have shown that RNA levels of the thiamine transporter THTR2 were down-regulated in breast cancer tumors in comparison with normal tissues and that THTR2-mediated increases in thiamine uptake activity contributed to increased apoptosis after exposure to ionizing radiation. To further understand the biological effects of the alteration of THTR2 expression, we conducted a DNA microarray study of gene expression in THTR2-transfected breast cancer cells and found that, in addition to increased expression of THTR2 attributable to the transgene, three other genes were up-regulated >2.5-fold in the transfected cells: cytochrome P450 isoform CYP4B1, 15-hydroxyprostaglandin dehydrogenase (15-PGDH), and transcription factor CRIP1. In addition, two genes were confirmed to be down-regulated in THTR2-transfected cells: trefoil factor 1 (TFF1) and Rho-GDP dissociation inhibitor (RGDI). Up-regulation of 15-PGDH and CYP4B1 expression was observed in other breast cancer cell lines transfected with THTR2, and down-regulation was observed after suppression of THTR2 with siRNA vectors. To determine the role of exogenous thiamine in the expression of these genes, we analyzed THTR2-transfected breast cancer cells grown in thiamine-depleted medium by quantitative reverse transcription-PCR and showed that three of these five genes showed evidence of regulation by exogenous thiamine in a manner concordant with the effects of THTR2 overexpression. One of the genes up-regulated by THTR2 transfection was down-regulated by thiamine depletion (CYP4B1), and two genes with decreased expression in THTR2-transfected breast cancer cells were up-regulated by thiamine depletion (TFF1 and RGDI). In summary, these studies show unexpected relationships between thiamine metabolism and genes that may be involved in the oncogenesis of breast and lung cancer.

Male infertility and thiamine-dependent erythroid hypoplasia in mice lacking thiamine transporter Slc19a2

Thiamine-responsive megaloblastic anemia with diabetes and deafness (TRMA) is an autosomal recessive disease caused by mutations in the high-affinity thiamine transporter gene SLC19A2. To study the role of thiamine transport in the pathophysiology of TRMA syndrome and of each of the component disorders, we created a targeted disruption of the Slc19a2 gene in mice. Slc19a2 −/− mice are viable and females are fertile. Male −/− mice on a pure 129/Sv background are infertile with small testes (testis/body weight=0.13 ± 0.04 knockout vs. 0.35 ± 0.05 wild type, P<0.000005). The lack of developing germ cells beyond primary spermatocytes suggests an arrest in spermatogenesis prior to meiosis II. Nuclear chromatin changes indicative of apoptosis are present. No mature sperm are found in the tubules or epididymis. This phenotype suggests a previously unknown role for thiamine transport in spermatogenesis and male fertility. Slc19a2 −/− mice on a pure 129/Sv background develop reticulocytopenia after two weeks on thiamine-depleted chow with a virtual absence of reticulocytes in the peripheral blood (0.12% knockout vs. 2.58% wild type, P=0.0079). Few erythroid precursors are found in the bone marrow. Contrary to human TRMA syndrome, we see no evidence of megaloblastosis or ringed sideroblasts in the bone marrow of Slc19a2 −/− mice in thiamine-replete or thiamine-deficient dietary states. Phenotypic differences between TRMA patients and Slc19a2 −/− mice might be explained by dissimilar tissue expression patterns of the transporter, as well as by differing metabolic needs and possible different species-specific contributions of the related thiamine transporter Slc19a3.

Identification of transcriptional start sites and splicing of mouse thiamine transporter gene THTR-1 ( Slc19a2)

We have previously reported the cDNA cloning of the mouse thiamine transporter THTR-1 as a p53 transcriptional target gene (renamed THTR-1a hereinafter). The mouse THTR-1a is predicted to encode a protein of 12 hydrophobic stretches and a hydrophilic loop of 87 amino acids between transmembrane helices VI and VII. The mouse THTR-1 gene has been cloned, two major transcriptional start sites located at −175 and −183 relative to the translation start codon were identified. In addition, we have cloned a spliced variant, designated THTR-1b, from mouse liver cDNA library. This isoform is characterized by an inframe deletion of 114 nucleotides from the 3′-terminal region of exon 2, predicting the expression of a truncated protein lacking the central 38 amino acids of the loop region. THTR-1b coexpressed with THTR-1a in many of the mouse tissues and in day-7 to day-17 embryos, but in lower levels than the THTR-1a. When expressed in mammalian cells, both isoforms were able to mediate the transport of thiamine. Therefore, the transport function of the mouse THTR-1 is not determined by the central 38 amino acids of its loop region.

Identification of a Mouse Thiamine Transporter Gene as a Direct Transcriptional Target for p53

p53 tumor suppressor is a transcription factor that functions, in part, through many of its downstream target genes. We have identified a p53-inducible gene by performing mRNA differential display on IW32 murine erythroleukemia cells containing a temperature-sensitive p53 mutant allele, tsp53(Val-135). Sequence analysis of the full-length cDNA revealed its identity as the mouse homologue of the human thiamine transporter 1 (THTR-1). Induction of the mouse THTR-1 (mTHTR-1) mRNA was detectable as early as 1 h at 32.5 degrees C; upon shifting back to 38.5 degrees C, mTHTR-1 transcript was rapidly degraded with a half-life of less than 2 h. Elevation of mTHTR-1 expression was found in DNA damage-induced normal mouse embryonic fibroblast cells, but not in p53(-/-) mouse embryonic fibroblast cells, suggesting that mTHTR-1 induction was p53-dependent. A region within the first intron of the mTHTR-1 gene bound to p53 and conferred the p53-mediated transactivation. Furthermore, increased thiamine transporter activities were found in cells overexpressing mTHTR-1 and under conditions of DNA damage or p53 activation. Our findings indicate that p53 may be involved in maintaining thiamine homeostasis through transactivation of THTR-1.