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The gene mutated in thiamine-responsive anaemia with diabetes and deafness (TRMA) encodes a functional thiamine transporter

Nature Genetics volume 22, pages 305–308 (1999)Cite this article

Abstract

Thiamine-responsive megaloblastic anaemia with diabetes and deafness1 (TRMA; MIM 249270) is an autosomal recessive disease thought to be due to a defect in thiamine (vitamin B1) transport2,3. Pharmacological doses of thiamine correct the anaemia, and in some cases improve the diabetes, although progressive sensorineural deafness is irreversible4. Previous studies localized the TRMA gene to a 4-cM region on chromosome 1q23.3 (ref. 5), and fine-mapping has recently narrowed that region further6,7. We have previously demonstrated that fibroblasts from people with TRMA lack high-affinity thiamine transport8. Expression of a gene encoding a known yeast thiamine transporter, THI10 (refs 8,9,10), in TRMA mutant cells prevents apoptotic cell death in thiamine-depleted medium. On the basis of these studies, we hypothesized that a defective thiamine transporter causes TRMA. We undertook a candidate gene approach to identify putative thiamine transporters in the 1q23.3 critical region. Here we present evidence that the gene SLC19A2 (for solute carrier family 19 (thiamine transporter), member 2) encodes the first known mammalian thiamine transporter, which we designate thiamine transporter-1 (THTR-1).

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Figure 1: Primer extension analysis of SLC19A2 cDNA.
Figure 2: Relationship of THTR-1 to similar proteins.
Figure 3: Expression of SLC19A2 message.
Figure 4: Mutations in SLC19A2 in two affected families.
Figure 5: THTR-1 directs high-affinity thiamine uptake.

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References

  1. Rogers, L.E., Porter, F.S. & Sidbury, J.B.J. Thiamine-responsive megaloblastic anemia. J. Pediatr. 74, 494–504 (1969).

    Article  Google Scholar 

  2. Poggi, V. et al. Thiamin-responsive megaloblastic anemia: a disorder of thiamin transport? J. Inherit. Metab. Dis. 7 (suppl. 2), 153–154 (1984).

    PubMed  Google Scholar 

  3. Rindi, G. et al. Thiamine transport by erythrocytes and ghosts in thiamine-responsive megaloblastic anemia. J. Inherit. Metab. Dis. 15, 231–242 (1992).

    Article  CAS  Google Scholar 

  4. Neufeld, E.J. et al. Localization of the gene for thiamine-responsive anemia syndrome on the long arm of chromosome 1 by homozygosity mapping. Am. J. Hum. Genet. 61, 1335–1341 (1997).

    Article  CAS  Google Scholar 

  5. Raz, T. et al. Refined mapping of the gene for thiamine-responsive megaloblastic anemia syndrome and evidence for genetic homogeneity. Hum. Genet. 103, 455–461 ( 1998).

    Article  CAS  Google Scholar 

  6. Banikazemi, M. et al. Localization of the thiamine-responsive megaloblastic anemia syndrome locus to a 1.4-cM region of 1q23. Mol. Genet. Metab. 66, 193–198 (1999).

    Article  CAS  Google Scholar 

  7. Labay, V. et al. Mutations in SLC19A2 cause thiamine-responsive megaloblastic anemia associated with diabetes mellitus and deafness. Nature Genet. 22, 300–304 ( 1999).

    Article  CAS  Google Scholar 

  8. Stagg, A.R. et al. Defective high-affinity thiamine transporter leads to cell death in thiamine-responsive megaloblastic anemia syndrome fibroblasts. J. Clin. Invest. 103, 723–729 (1999).

    Article  CAS  Google Scholar 

  9. Enjo, F., Nosaka, K., Ogata, M., Iwashima, A. & Nishimura, H. Isolation and characterization of a thiamine transport gene, THI10, from Saccharomyces cerevisiae. J. Biol. Chem. 272, 19165–19170 ( 1997).

    Article  CAS  Google Scholar 

  10. Singleton, C.K. Identification and characterization of the thiamine transporter gene of Saccharomyces cerevisiae. Gene 199, 111–121 (1997).

    Article  CAS  Google Scholar 

  11. Altschul, S.F. et al. Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res. 25, 3389–3402 (1997).

    Article  CAS  Google Scholar 

  12. Prasad, P.D., Ramamoorthy, S., Leibach, F.H. & Ganapathy, V. Molecular cloning of the human placental folate transporter. Biochem. Biophys. Res. Commun. 206, 681–687 (1995).

    Article  CAS  Google Scholar 

  13. Wong, S.C., Proefke, S.A., Bhushan, A. & Matherly, L.H. Isolation of human cDNAs that restore methotrexate sensitivity and reduced folate carrier activity in methotrexate transport-defective Chinese hamster ovary cells. J. Biol. Chem. 270, 17468– 17475 (1995).

    Article  CAS  Google Scholar 

  14. Rost, B., Casadio, R., Fariselli, P. & Sander, C. Transmembrane helices predicted at 95% accuracy. Protein Sci. 4, 521–533 (1995).

    Article  CAS  Google Scholar 

  15. Sambrook, J., Fritsch, E.F. & Maniatis, T. Molecular Cloning. A Laboratory Manual (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, 1989).

    Google Scholar 

  16. Fleming, M.D. et al. Nramp2 is mutated in the anemic Belgrade (b) rat: evidence of a role for Nramp2 in endosomal iron transport. Proc. Natl Acad. Sci. USA 95, 1148–1153 ( 1998).

    Article  CAS  Google Scholar 

  17. Bairoch, A., Bucher, P. & Hofman, K. The PROSITE database, its status in 1997. Nucleic Acids Res. 25, 217–221 (1997).

    Article  CAS  Google Scholar 

  18. Bonthron, D.T. et al. Structure of pre-pro-von Willebrand factor and its expression in heterologous cells. Nature 324, 270– 273 (1986).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank M. Fleming for helpful advice, A. Stagg for technical assistance, D. Fenske, and patients and their families. This work was supported by the March of Dimes (E.J.N.) and NIH training grant T32 HL07574 (J.C.F.).

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Authors and Affiliations

  1. Division of Hematology, Children's Hospital, Dana Farber Cancer Institute, and Harvard Medical School, Boston, 02115, Massachusetts, USA

    Judith C. Fleming, Elena Tartaglini, Mara P. Steinkamp & Ellis J. Neufeld

  2. Institute of Biochemistry, University of Ancona, Ancona, 60100, Italy

    Elena Tartaglini

  3. Division of Medical Genetics, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, 1011, Switzerland

    Daniel F. Schorderet

  4. Department of Genetics, Tamkin Human Molecular Genetics Research Facility, Technion-Israel Institute of Technology, Bruce Rappaport Faculty of Medicine, POB 9649, Haifa, 31096, Israel

    Nadine Cohen

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  1. Judith C. Fleming
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  6. Ellis J. Neufeld
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Correspondence to Ellis J. Neufeld.

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Fleming, J., Tartaglini, E., Steinkamp, M. et al. The gene mutated in thiamine-responsive anaemia with diabetes and deafness (TRMA) encodes a functional thiamine transporter. Nat Genet 22, 305–308 (1999). https://doi.org/10.1038/10379

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