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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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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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