Mutations in CUBN, encoding the intrinsic factor-vitamin B12 receptor, cubilin, cause hereditary megaloblastic anaemia 1 (original) (raw)

Nature Genetics volume 21, pages 309–313 (1999)Cite this article

Abstract

Megaloblastic anaemia 1 (MGA1, OMIM 261100) is a rare, autosomal recessive disorder characterized by juvenile megaloblastic anaemia, as well as neurological symptoms that may be the only manifestations1,2. At the cellular level, MGA1 is characterized by selective intestinal vitamin B12 (B12, cobalamin) malabsorption2. MGA1 occurs worldwide, but its prevalence is higher in several Middle Eastern countries3,4,5,6 and Norway1,7, and highest in Finland8 (0.8/100,000). We previously mapped the MGA1 locus by linkage analysis in Finnish and Norwegian families to a 6-cM region on chromosome 10p12.1 (ref. 8). A functional candidate gene encoding the intrinsic factor (IF)-B12 receptor, cubilin, was recently cloned9,10; the human homologue, CUBN, was mapped to the same region10. We have now refined the MGA1 region by linkage disequilibrium (LD) mapping, fine-mapped CUBN and identified two independent disease-specific CUBN mutations in 17 Finnish MGA1 families. Our genetic and molecular data indicate that mutations in CUBN cause MGA1.

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Acknowledgements

We thank the patients and their families for continued cooperation; S. Lindh for assistance with sample collection; L. Aaltonen and P. Peltomäki for providing control DNA samples; F. Wright and X. Gao for statistical advice and support; and K. Virtaneva and C. Plass for critical reading of the manuscript. M.A. and A.d.l.C. were supported by the Ulla Hjelt Fund, Liv och Hälsa and the Academy of Finland. This study was supported in part by grant P30 CA16058, National Cancer Institute.

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Authors and Affiliations

  1. Division of Human Cancer Genetics, Department of Medical Microbiology and Immunology, Comprehensive Cancer Center, Ohio State University, Columbus, 43210, Ohio, USA
    Maria Aminoff, Jo Ellen Carter, Robert B. Chadwick, Cheryl Johnson, Albert de la Chapelle & Ralf Krahe
  2. Department of Medical Genetics, Folkhälsan Institute of Genetics, University of Helsinki, Helsinki, FIN-00280, Finland
    Maria Aminoff, Albert de la Chapelle & Ralf Krahe
  3. Minerva Foundation Institute for Medical Research, Helsinki, FIN-00250, Finland
    Ralph Gräsbeck
  4. Department of Pathology, National Guard King Khalid Hospital, Jeddah, 21423, Saudi Arabia
    Mohamed A. Abdelaal
  5. Department of Pediatrics, Vestfold Central Hospital, Toensberg, N-3103, Norway
    Harald Broch
  6. Department of Molecular and Structural Biology, University of Aarhus, Aarhus C, DK-8000, Denmark
    Lasse B. Jenner
  7. INSERM U 489, Hopital Tenon, Paris, F-75020, France
    Pierre J. Verroust
  8. Department of Medical Biochemistry, University of Aarhus, Aarhus C, DK-8000, Denmark
    Soeren K. Moestrup

Authors

  1. Maria Aminoff
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  2. Jo Ellen Carter
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  3. Robert B. Chadwick
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  4. Cheryl Johnson
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  5. Ralph Gräsbeck
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  6. Mohamed A. Abdelaal
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  7. Harald Broch
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  8. Lasse B. Jenner
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  9. Pierre J. Verroust
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  10. Soeren K. Moestrup
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  11. Albert de la Chapelle
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  12. Ralf Krahe
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Correspondence toRalf Krahe.

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Aminoff, M., Carter, J., Chadwick, R. et al. Mutations in CUBN, encoding the intrinsic factor-vitamin B12 receptor, cubilin, cause hereditary megaloblastic anaemia 1.Nat Genet 21, 309–313 (1999). https://doi.org/10.1038/6831

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