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

Abstract	Thiamine-responsive megaloblastic anaemia (TRMA), also known as Rogers syndrome, is an early onset, autosomal recessive disorder defined by the occurrence of megaloblastic anaemia, diabetes mellitus and sensorineural deafness, responding in varying degrees to thiamine treatment (MIM 249270). We have previously narrowed the TRMA locus from a 16-cM to a 4-cM interval on chromosomal region 1q23.3 (refs 3,4) and this region has been further refined to a 1.4-cM interval. Previous studies have suggested that deficiency in a high-affinity thiamine transporter may cause this disorder. Here we identify the TRMA gene by positional cloning. We assembled a P1-derived artificial chromosome (PAC) contig spanning the TRMA candidate region. This clarified the order of genetic markers across the TRMA locus, provided 9 new polymorphic markers and narrowed the locus to an approximately 400-kb region. Mutations in a new gene, SLC19A2, encoding a putative transmembrane protein homologous to the reduced folate carrier proteins, were found in all affected individuals in six TRMA families, suggesting that a defective thiamine transporter protein (THTR-1) may underlie the TRMA syndrome.
Authors	V Labay, T Raz, D Baron, H Mandel, H Williams, T Barrett, R Szargel, L McDonald, A Shalata, K Nosaka, S Gregory, N Cohen
Journal	Nature genetics (Nat Genet) Vol. 22 Issue 3 Pg. 300-4 (Jul 1999) ISSN: 1061-4036 [Print] United States
PMID	10391221 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Carrier Proteins DNA Primers Genetic Markers Membrane Transport Proteins SLC19A2 protein, human Slc19a2 protein, mouse DNA Thiamine
Topics	Amino Acid Sequence Anemia, Megaloblastic (complications, drug therapy, genetics) Animals Base Sequence Carrier Proteins (genetics) Cricetinae DNA (genetics) DNA Primers (genetics) Deafness (complications, genetics) Diabetes Complications Diabetes Mellitus (genetics) Female Genes, Recessive Genetic Markers Humans Male Membrane Transport Proteins Mice Molecular Sequence Data Mutation Physical Chromosome Mapping Sequence Homology, Amino Acid Syndrome Thiamine (metabolism, therapeutic use)

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