SLC19A2

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).

Abstract: Thiamine-responsive megaloblastic anaemia syndrome (TRMA; MIM 249270) is an autosomal recessive disorder with features that include megaloblastic anaemia, mild thrombocytopenia and leucopenia, sensorineural deafness and diabetes mellitus1,2,3 Treatment with pharmacologic doses of thiamine ameliorates the megaloblastic anaemia and diabetes mellitus A defect in the plasma membrane transport of thiamine has been demonstrated in erythrocytes and cultured skin fibroblasts from TRMA patients4,5,6 The gene causing TRMA was assigned to 1q232–q233 by linkage analysis7 Here we report the cloning of a new gene, SLC19A2, identified from high-throughput genomic sequences due to homology with SLC19A1, encoding reduced folate carrier 1 (refs 8,9,10)We cloned the entire coding region by screening a human fetal brain cDNA library SLC19A2 encodes a protein (of 497 aa) predicted to have 12 transmembrane domains We identified 2 frameshift mutations in exon 2, a 1-bp insertion and a 2-bp deletion, among four Iranian families with TRMA The sequence homology and predicted structure of SLC19A2, as well as its role in TRMA, suggest that its gene product is a thiamine carrier, the first to be identified in complex eukaryotes