Mutations in SLC19A2 cause thiamine-responsive megaloblastic anaemia associated with diabetes mellitus and deafness.
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.
Labay
V
V
Department of Genetics, Tamkin Human Molecular Genetics Research Facility, Technion-Israel Institute of Technology, Bruce Rappaport Faculty of Medicine, Haifa.
Raz
T
T
Baron
D
D
Mandel
H
H
Williams
H
H
Barrett
T
T
Szargel
R
R
McDonald
L
L
Shalata
A
A
Nosaka
K
K
Gregory
S
S
Cohen
N
N
D000595:Amino Acid Sequence; D000749:Anemia, Megaloblastic / Q000150:complications / Q000188:drug therapy / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics; D006224:Cricetinae; D004247:DNA / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D003638:Deafness / Q000150:complications / Q000235:genetics*; D048909:Diabetes Complications; D003920:Diabetes Mellitus / Q000235:genetics*; D005260:Female; D005808:Genes, Recessive; D005819:Genetic Markers; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D020161:Physical Chromosome Mapping; D017386:Sequence Homology, Amino Acid; D013577:Syndrome; D013831:Thiamine / Q000378:metabolism / Q000627:therapeutic use
D002352:Carrier Proteins; D017931:DNA Primers; D005819:Genetic Markers; D026901:Membrane Transport Proteins; C120043:SLC19A2 protein, human; C492292:Slc19a2 protein, mouse; D004247:DNA; D013831:Thiamine