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

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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Figure 1: Genetic and physical map of the MGA1 region.
Figure 2: Identification of the 3916C→T missense mutation (FM1) in CUBN associated with MGA1.
Figure 3: Identification of the second Finnish (FM2) mutation found in a single MGA1 kindred.
Figure 4: Three-dimensional modelling of mutant (FM1) CUB domain 8 with P1297L based on the X-ray structure of a CUB domain from spermadhesin 1 SPP (refs 16,26).
Figure 5: Expression analysis of cubilin protein.

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References

  1. Imerslund, O. Idiopathic chronic megaloblastic anemia in children. Acta Paediatr. 49 (suppl.), 208–209 (1960).

    Article  Google Scholar 

  2. Gräsbeck, R., Gordon, R., Kantero, I. & Kuhlback, B. Selective vitamin B12 malabsorption and proteinuria in young people. Acta Med. Scand. 167, 289–296 (1960).

    Article  Google Scholar 

  3. Ben-Bassat, I., Feinstein, A. & Ramot, B. Selective vitamin B12 malabsorption with proteinuria in Israel: clinical and genetic aspects. Isr. J. Med. Sci. 5, 62–68 (1969).

    CAS  Google Scholar 

  4. Abdelaal, M.A. & Ahmed, A.F. Imerslund-Gräsbeck syndrome in a Saudi family. Acta Paediatr. 80, 1109 –1112 (1991).

    Article  CAS  Google Scholar 

  5. Altay, C. et al. Familial selective vitamin B12 malabsorption (Imerslund-Gräsbeck syndrome) in a pool of Turkish patients. Pediatr. Hematol. Oncol. 12, 19–28 (1995).

    Article  CAS  Google Scholar 

  6. Ismail, E.A., Al Saleh, Q., Sabry, M.A., Al Ghanim, M. & Zaki, M. Genotypic/phenotypic heterogeneity of selective vitamin B12 malabsorption (Gräsbeck-Imerslund syndrome) in two Bedouin families. Acta Paediatr. 86, 424–425 (1997).

    Article  CAS  Google Scholar 

  7. Broch, H., Imerslund, O., Monn, E., Hovig, T. & Seip, M. Imerslund-Gräsbeck anemia: a long-term follow-up study. Acta Paediatr. 73, 248–253 (1984).

    Article  CAS  Google Scholar 

  8. Aminoff, M. et al. Selective intestinal malabsorption of vitamin B12 displays recessive mendelian inheritance: assignment of a locus to chromosome 10 by linkage. Am. J. Hum. Genet. 57, 824– 831 (1995).

    CAS  Google Scholar 

  9. Moestrup, S.K. et al. The intrinsic factor-vitamin B12 receptor and target of teratogenic antibodies is a megalin-binding peripheral membrane protein with homology to developmental proteins. J. Biol. Chem. 273, 5235–5242 (1998).

    Article  CAS  Google Scholar 

  10. Kozyraki, R. et al. The human intrinsic factor-vitamin B12 receptor, cubilin: molecular characterization and chromosomal mapping of the gene to 10p within the autosomal recessive megaloblastic anemia (MGA1) region. Blood 91, 3593–3600 (1998).

    CAS  Google Scholar 

  11. Burman, J.F. et al. Absent ileal uptake of IF-bound vitamin B12 in vivo in the Imerslund-Gräsbeck syndrome (familial vitamin B12 malabsorption with proteinuria). Gut 26, 311– 314 (1985).

    Article  CAS  Google Scholar 

  12. Dugue, B. et al. A urinary radioisotope-binding assay to diagnose Gräsbeck-Imerslund disease. J. Pediatr. Gastroenterol. Nutr. 26, 21–25 (1998).

    Article  CAS  Google Scholar 

  13. Gräsbeck, R. Selective cobalamin malabsorption and the cobalamin-intrinsic factor receptor. Acta Biochim. Pol. 44, 725– 735 (1997).

    Google Scholar 

  14. Moestrup, S.K. et al. Megalin-mediated endocytosis of transcobalamin-vitamin-B12 complexes suggests a role of the receptor in vitamin-B12 homeostasis. Proc. Natl Acad. Sci. USA 93, 8612– 8617 (1996).

    Article  CAS  Google Scholar 

  15. Birn, H. et al. Characterization of an epithelial approximately 460-kDa protein that facilitates endocytosis of intrinsic factor-vitamin B12 and binds receptor-associated protein. J. Biol. Chem. 272, 26497– 26504 (1997).

    Article  CAS  Google Scholar 

  16. Bork, P. & Beckmann, G. The CUB domain. A widespread module in developmentally regulated proteins. J. Mol. Biol. 231, 539–545 (1993).

    Article  CAS  Google Scholar 

  17. Moestrup, S.K. & Verroust, P.J. Mammalian receptors of vitamin B12 binding protein. in Chemistry and Biochemistry of B12 (ed. Banerjee, R.) (John Wiley and Sons, New York, in press).

  18. de la Chapelle, A. & Wright, F.A. Linkage disequilibrium mapping in isolated populations: the example of Finland revisited. Proc. Natl Acad. Sci. USA 95, 12416– 12423 (1998).

    Article  CAS  Google Scholar 

  19. Furuhjelm, U. & Nevanlinna, H.R. Inheritance of selective malabsorption of vitamin B12. Scand. J. Haematol. 11, 27–34 (1973).

    Article  CAS  Google Scholar 

  20. Höglund, P. et al. Intestinal anion transport: mutations in the down-regulated in adenoma (DRA) gene cause congenital chloride diarrhoea. Nature Genet. 14, 316–319 (1996).

    Article  Google Scholar 

  21. MacKenzie, I.L., Donaldson, R.M., Trier, J.S. & Mathan, V.I. Ileal mucosa in familial selective vitamin B12 malabsorption. N. Engl. J. Med. 286, 1021–1025 (1972).

    Article  CAS  Google Scholar 

  22. 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 

  23. Hudson, T.J. et al. An STS-based map of the human genome. Science 270, 1945–1954 (1995).

    Article  CAS  Google Scholar 

  24. Phelps, R.S., Chadwick, R.B., Conrad, M.P., Kronick, M.N. & Kamb, A. Efficient, automatic detection of heterozygous bases during large-scale DNA sequence screening. Biotechniques 19, 984–989 (1995).

    CAS  Google Scholar 

  25. Sahali, D. et al. Coexpression in humans by kidney and fetal envelopes of a 280 kDa-coated pit-restricted protein. Similarity with the murine target of teratogenic antibodies. Am. J. Pathol. 140, 33–44 (1992).

    CAS  Google Scholar 

  26. Romero, A. et al. The crystal structures of two spermadhesins reveal the CUB domain fold. Nature Struct. Biol. 4, 783 –788 (1997).

    Article  CAS  Google Scholar 

  27. Jones, T.A., Zou, J.Y., Cowan, S.W. & Kjeldgaard, M. Improved methods for binding protein models in electron density maps and the location of errors in these models. Acta Crystallogr. A 47, 110–119 (1991).

    Article  Google Scholar 

  28. Kraulis, P.J. MOLSCRIPT: A program to produce both detailed and schematic plots of protein structures. J. Appl. Cryst. 47, 110– 119 (1991).

    Google Scholar 

  29. Merrit, E.A. & Murphy, M.E.P. Raster3D Version 2.0: a program for photorealistic molecular graphics. Acta Crystallogr. D 50, 869–873 (1994).

    Article  Google Scholar 

  30. Gyapay, G. et al. A radiation hybrid map of the human genome. Hum. Mol. Genet. 5, 339–346 (1996).

    Article  CAS  Google Scholar 

Download references

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

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  1. Maria Aminoff
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Correspondence to Ralf 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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