Mutations in SLC19A2 cause thiamine-responsive megaloblastic anaemia associated with diabetes mellitus and deafness

Labay, Valentina; Raz, Tal; Baron, Dana; Mandel, Hanna; Williams, Hawys; Barrett, Timothy; Szargel, Raymonde; McDonald, Louise; Shalata, Adel; Nosaka, Kazuto; Gregory, Simon G.; Cohen, Nadine

doi:10.1038/10372

Cited by 244 publications

(186 citation statements)

References 17 publications

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“…6). In 1999, the gene responsible was identified by three independent groups to encode a solute carrier protein, called THTR1 (2,3,5). This gene was cloned from a human fetal brain cDNA library and termed SLC19A2 (5).…”

Section: Discussionmentioning

confidence: 99%

“…In July 2005, she presented with fever and severe anemia. She was found to have hyperglycemia of 29 mmol/l and moderate diabetic ketoacidosis (pH 7.16, HCO 3 14, serum and urine ketones CC). Investigations at that time showed: leucocyte count 24 000 cells/dl, hemoglobin 3 g/dl, MCV 78, MCH 27, platelets 28 000, reticulocyte count 61 , creatinine 49 mmol/l, HbA1c 12%, hemoglobin electrophoresis was normal, serum iron 20 mol/l (6-27), iron saturation 0.91 (0.08-0.41), serum ferritin 3773 g/l (13-150), vitamin B12, and red blood cell folate were normal.…”

Section: Case Reportmentioning

confidence: 99%

“…It is inherited in an autosomal recessive pattern. Unlike the familiar forms of diabetes in which polygenetic and environmental factors interact, diabetes in TRMA syndrome is a monogenic form of diabetes secondary to mutations in the SLC19A2 gene, which encodes a plasma membrane thiamine transporter, called THTR1 (2)(3)(4)(5)(6). The latter is a member of the solute carrier family that includes its homolog THTR2 and the reduced folate carrier.…”

Section: Introductionmentioning

confidence: 99%

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Thiamine transporter mutation: an example of monogenic diabetes mellitus

Alzahrani

Baitei²,

Zou³

et al. 2006

eur j endocrinol

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Objective: 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. Case: The patient is an 18-year-old girl who was born to non-consanguous parents. She was noted to be deafmute 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. Methods: Peripheral blood DNAwas 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. Results: 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. Conclusions: 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.European Journal of Endocrinology 155 787-792

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Section: Discussionmentioning

confidence: 99%

Section: Case Reportmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Thiamine transporter mutation: an example of monogenic diabetes mellitus

Alzahrani

Baitei²,

Zou³

et al. 2006

eur j endocrinol

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“…The gene responsible (SLC19A2) encodes a high-affinity thiamine transporter (Diaz et al 1999;Fleming et al 1999;Labay et al 1999). Within the cochlea, this high-affinity transporter is expressed in inner hair cells (IHC) (Fleming et al 2001).…”

Section: Introductionmentioning

confidence: 99%

Deletion of SLC19A2, the High Affinity Thiamine Transporter, Causes Selective Inner Hair Cell Loss and an Auditory Neuropathy Phenotype

Liberman

Tartaglini

Fleming

et al. 2006

JARO

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Mutations in the gene coding for the high-affinity thiamine transporter Slc19a2 underlie the clinical syndrome known as thiamine-responsive megaloblastic anemia (TRMA) characterized by anemia, diabetes, and sensorineural hearing loss. To create a mouse model of this disease, a mutant line was created with targeted disruption of the gene. Cochlear function is normal in these mutants when maintained on a high-thiamine diet. When challenged with a low-thiamine diet, Slc19a2-null mice showed 40-60 dB threshold elevations by auditory brainstem response (ABR), but only 10-20 dB elevation by otoacoustic emission (OAE) measures. Wild-type mice retain normal hearing on either diet. Cochlear histological analysis showed a pattern uncommon for sensorineural hearing loss: selective loss of inner hair cells after 1-2 weeks on low thiamine and significantly greater inner than outer hair cell loss after longer low-thiamine challenges. Such a pattern is consistent with the observed discrepancy between ABR and OAE threshold shifts. The possible role of thiamine transport in other reported cases of selective inner hair cell loss is considered.

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“…identified a direct transcriptional target gene of p53 by the method of mRNA differential display (30). Sequence analysis revealed its identity to be the mouse orthologue of the newly identified human THTR-1 1 (31)(32)(33)(34). We have shown that THTR-1 gene was induced under DNA damage in a p53-dependent manner; moreover, increased thiamine uptake activity correlated with p53 activation.…”

mentioning

confidence: 81%

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

Lo¹,

Chen²,

Tang³

et al. 2001

Journal of Biological Chemistry

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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 . Sequence analysis of the fulllength 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°C; upon shifting back to 38.5°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.

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Mutations in SLC19A2 cause thiamine-responsive megaloblastic anaemia associated with diabetes mellitus and deafness

Cited by 244 publications

References 17 publications

Thiamine transporter mutation: an example of monogenic diabetes mellitus

Thiamine transporter mutation: an example of monogenic diabetes mellitus

Deletion of SLC19A2, the High Affinity Thiamine Transporter, Causes Selective Inner Hair Cell Loss and an Auditory Neuropathy Phenotype

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

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