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

Nature Genetics volume 22, pages 300–304 (1999)Cite this article

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 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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Figure 1: Genomic organization of the TRMA candidate interval.
Figure 2: Haplotypes of key patients from the six families.
Figure 3: RNA expression levels, protein sequence and topology.
Figure 4: DNA sequence electrophoregrams showing the four mutations.

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References

  1. Rogers, L.E., Porter, F.S. & Sidbury, J.B. Jr Thiamine-responsive megaloblastic anemia. J. Pediatr. 74, 494– 504 (1969).

    Article  Google Scholar 

  2. Mandel, H., Berant, M., Hazani, A. & Naveh, Y. Thiamine-dependent beriberi in the thiamine-responsive anemia syndrome. N. Engl. J. Med. 311, 836–838 ( 1984).

    Article  CAS  Google Scholar 

  3. Neufeld, E.J. et al. Localization of the gene for thiamine-responsive megaloblastic anemia syndrome on the long arm of chromosome 1 by homozygosity mapping. Am. J. Hum. Genet. 61, 1335–1341 (1997).

    Article  CAS  Google Scholar 

  4. Raz, T. et al. Refine mapping of the gene for thiamine-responsive megaloblastic anemia syndrome in a 4cM region and evidence for genetic homogeneity. Hum. Genet. 103, 455–461 (1998).

    Article  CAS  Google Scholar 

  5. Banikazemi, M. et al. Localization of the thiamine-responsive megaloblastic anemia syndrome locus to a 1.4-cM region of 1q23. Mol. Genet. Metab. 66, 193–198 (1999).

    Article  CAS  Google Scholar 

  6. Rindi, G. et al. Further studies on erythrocyte thiamine transport and phosphorylation in seven patients with thiamine-responsive megaloblastic anemia. J. Inher. Metab. Dis. 17, 667–677 (1994).

    Article  CAS  Google Scholar 

  7. Stagg, A.R. et al. Defective high-affinity transporter leads to cell death in TRMA syndrome fibroblasts. J. Clin. Invest. 103, 723–729 (1999).

    Article  CAS  Google Scholar 

  8. Wong, S.C., Proefke, S.A., Bhushan, A. & Matherly, L.H. Isolation of human cDNAs that restore methotrexate sensitivity and reduced folate carrier activity in methotrexate transport-defective Chinese hamster ovary cells. J. Biol. Chem. 270, 17468– 17475 (1995).

    Article  CAS  Google Scholar 

  9. Prasad, P.D., Ramamoorthy, S., Leibach, F.H. & Ganapathy, V. Molecular cloning of the human placental folate transporter. Biochem. Biophys. Res. Commun. 206, 681–687 (1995).

    Article  CAS  Google Scholar 

  10. Altschul, S.F., Gish, W., Miller, E.W. & Lipman, D.J. Basic local alignment search tool. J. Mol. Biol. 215, 403– 410 (1990).

    Article  CAS  Google Scholar 

  11. Kozak, M. Interpreting cDNA sequences: some insights from studies on translation. Mamm. Genome 7, 563–574 (1996).

    Article  CAS  Google Scholar 

  12. Fleming, J.C. et al. The gene mutated in thiamine-responsive anaemia with diabetes and deafness (TRMA) encodes a functional thiamine transporter Nature Genet. 22, 305–308 (1999).

    Article  CAS  Google Scholar 

  13. Hanson, R.L. et al. An autosomal genomic scan for loci linked to type II diabetes mellitus and body-mass index in Pima Indians. Am. J. Hum. Genet. 63, 1130–1138 ( 1998).

    Article  CAS  Google Scholar 

  14. Concannon, P. et al. A second-generation screen of the human genome for susceptibility to insulin-dependent diabetes mellitus. Nature Genet. 19, 292–296 (1998).

    Article  CAS  Google Scholar 

  15. Dib, C. et al. A comprehensive genetic map of the human genome based on 5,264 microsatellites. Nature 380, 152–154 (1996).

    Article  CAS  Google Scholar 

  16. Gyapay, G., Ginot, F., Nguyen, S., Vignal, A. & Weissenbach, J. Genotyping procedures in linkage mapping. Methods 9, 91–97 ( 1996).

    Article  CAS  Google Scholar 

  17. Boguski, M.S., Lowe, T.M.J. & Tolstoshev, C.M. dbEST-database for "expressed sequence tags". Nature Genet. 4, 332–333 (1993).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank the families; the Sanger Centre Mapping, Sequencing and Analysis teams, particularly C. Bird, for the finishing of PAC 206D15; S. Rhodes for the further analysis of the finished sequence; and E. Sprecher for critical reading of the manuscript. This work was supported by grants from the Juvenile Diabetes Foundation International, the Israeli Academy of Sciences and the Pittsburgh Technion Research Foundation (N.C.). V.L. is recipient of a post-doctoral fellowship from the Juvenile Diabetes Foundation International and from the Israeli Ministry of Sciences (in part).

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  1. Valentina Labay, Tal Raz and Dana Baron: These authors contributed equally to this work.

Authors and Affiliations

  1. 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

    Valentina Labay, Tal Raz, Dana Baron, Raymonde Szargel, Adel Shalata & Nadine Cohen

  2. Department of Pediatrics, Rambam Medical Center, Technion-Israel Institute of Technology, Bruce Rappaport Faculty of Medicine, Haifa, Israel

    Hanna Mandel

  3. The Sanger Centre, Wellcome Trust Genome Campus, Cambridge, England

    Hawys Williams, Louise McDonald & Simon Gregory

  4. Department of Pediatrics and Child Health, University of Birmingham, Birmingham, UK

    Timothy Barrett

  5. Kyoto Prefectural University of Medicine, Kyoto, Japan

    Kazuto Nosaka

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  1. Valentina Labay
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Correspondence to Nadine Cohen.

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Labay, V., Raz, T., Baron, D. et al. Mutations in SLC19A2 cause thiamine-responsive megaloblastic anaemia associated with diabetes mellitus and deafness. Nat Genet 22, 300–304 (1999). https://doi.org/10.1038/10372

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