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

Thiamine-responsive megaloblastic anaemia (TRMA), also known as Rogers synd rome, is an early onset, autosomal recessive disorder defined by the occurr ence megaloblastic anaemia, diabetes mellitus and sensorineural deafness. r esponding in varying degrees to thiamine treatment(1,2) (MIM 249270). We ha ve previously narrowed the TRMA locus from a 16-cM to a 4-cM interval on ch romosomal region 1q23.3 (refs 3,4) and this region has been further refined to a 1.4-cM interval(5). Previous studies have suggested that deficiency i n,a high-affinity thiamine transporter may cause this disorder(6,7). Here w e identify the TRMA gene by positional cloning. We assembled a P1-derived a rtificial chromosome (PAC) contig spanning the TRMA candidate region. This clarified the order of genetic markers across the TRMA locus, provided 9 ne w polymorphic markers and narrowed the locus to an approximately 400-kb reg ion. Mutations in a new gene, SLC19A2, encoding a putative transmembrane pr otein homologous to the reduced folate carrier protein(8,9), were found in all affected individuals in six TRMA families, suggesting that a defective thiamine transporter protein (THTR-1) may underlie the TRMA syndrome.