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Amnionless, essential for mouse gastrulation, is mutated in recessive hereditary megaloblastic anemia

Nature Genetics volume 33, pages 426429 (2003) | Download Citation



The amnionless gene, Amn, on mouse chromosome 12 encodes a type I transmembrane protein that is expressed in the extraembryonic visceral layer during gastrulation1. Mice homozygous with respect to the amn mutation generated by a transgene insertion have no amnion2,3. The embryos are severely compromised, surviving to the tenth day of gestation but seem to lack the mesodermal layers that normally produce the trunk4. The Amn protein has one transmembrane domain separating a larger, N-terminal extracellular region and a smaller, C-terminal cytoplasmic region. The extracellular region harbors a cysteine-rich domain resembling those occurring in Chordin, found in Xenopus laevis embryos, and Sog, found in Drosophila melanogaster. As these cysteine-rich domains bind bone morphogenetic proteins (Bmps), it has been speculated that the cysteine-rich domain in Amn also binds Bmps4. We show that homozygous mutations affecting exons 1–4 of human AMN lead to selective malabsorption of vitamin B12 (a phenotype associated with megaloblastic anemia 1, MGA1; OMIM 261100; refs. 5,6) in otherwise normal individuals, suggesting that the 5′ end of AMN is dispensable for embryonic development but necessary for absorption of vitamin B12. When the 5′ end of AMN is truncated by mutations, translation is initiated from alternative downstream start codons.

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We thank P. Lahermo and J. Kere of the Finnish Genome Center for genome-wide linkage analysis and advice; R. Gräsbeck, T. Joensuu, A.-E. Lehesjoki and G. Leone for ideas, suggestions and constructive criticism; Z. Li and R. Bisson for expert technical support with construct cloning; S. Lindh for sample collection; and K. Green-Church for protein mass spectrometry. This work was supported by the Liv och Hälsa Foundation and the US National Cancer Institute. S.M.T. is supported by the Swiss National Science Foundation and the Swiss Foundation for Medical-Biological Grants.

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  1. Human Cancer Genetics Program, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA.

    • Stephan M. Tanner
    • , Fred A. Wright
    • , Sandya Liyanarachchi
    •  & Albert de la Chapelle
  2. Folkhälsan Institute of Genetics, Department of Medical Genetics, University of Helsinki, Helsinki, Finland.

    • Maria Aminoff
    • , Mervi Kuronen
    •  & Anne Saarinen
  3. Metabolic Unit, Department of Pediatrics, Rambam Medical Center, Haifa, Israel.

    • Orit Massika
    •  & Hanna Mandel
  4. Department of Pediatrics, Vestfold Central Hospital, Toensberg, Norway.

    • Harald Broch


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The authors declare no competing financial interests.

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Correspondence to Albert de la Chapelle.

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