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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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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DOI: https://doi.org/10.1038/6831
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