Mutations in a new gene encoding a thiamine transporter cause thiamine-responsive megaloblastic anaemia syndrome

Thiamine-responsive megaloblastic anaemia syndrome (TRMA; MIM 249270) is an autosomal recessive disorder with features that include megaloblastic anae mia, mild thrombocytopenia and leucopenia, sensorineural deafness and diabe tes mellitus(1-3). Treatment with pharmacologic doses of thiamine ameliorat es the megaloblastic anaemia and diabetes mellitus. A defect in the plasma membrane transport of thiamine has been demonstrated in erythrocytes and cu ltured skin fibroblasts from TRMA patients(4-6). The gene causing TRMA was assigned to 1q23.2-q23.3 by linkage analysis(7). 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 8-10) . 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 transme mbrane domains. We identified 2 frameshift mutations in exon 2, a 1-bp inse rtion and a 2-bp deletion, among four Iranian families with TRMA. The seque nce homology and predicted structure of SLC19A2, as well as its role in TRM A, suggest that its gene product is a thiamine carrier, the first to be ide ntified in complex eukaryotes.