Nature Genetics
22, 300 - 304 (1999)
doi:10.1038/10372
Mutations in SLC19A2 cause thiamine-responsive megaloblastic anaemia
associated with diabetes mellitus and deafnessValentina Labay1, 6, Tal Raz1, 6, Dana Baron1, 6, Hanna Mandel2, Hawys Williams3, Timothy Barrett4, Raymonde Szargel1, Louise McDonald3, Adel Shalata1, Kazuto Nosaka5, Simon Gregory3
& Nadine Cohen11
Department of Genetics, Tamkin Human Molecular Genetics
Research Facility, Technion-Israel Institute of Technology, Bruce Rappaport
Faculty of Medicine, P.O. Box 9649, Haifa
31096, Israel. 2
Department of Pediatrics, Rambam Medical Center, Technion-Israel
Institute of Technology, Bruce Rappaport Faculty of Medicine,
Haifa, Israel. 3
The Sanger Centre, Wellcome Trust Genome Campus,
Cambridge, England. 4
University of Birmingham, Department of Pediatrics
and Child Health, Birmingham, UK. 5
Kyoto Prefectural University of Medicine,
Kyoto, Japan. 6
These authors contributed equally to this work.
Correspondence should be addressed to Nadine Cohen nadine@tx.technion.ac.ilThiamine-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 treatment1,
2 (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 interval5. Previous studies have suggested that deficiency in a high-affinity
thiamine transporter may cause this disorder6,
7. 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 proteins8,
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.
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