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Blood, 15 August 2005, Vol. 106, No. 4, pp. 1447-1453.
Prepublished online as a Blood First Edition Paper on April 21, 2005; DOI 10.1182/blood-2005-03-1197.
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Submitted March 24, 2005
Accepted April 13, 2005
Amnionless function is required for cubilin brush-border expression and intrinsic factor-cobalamin (vitamin B12) absorption in vivo
Qianchuan He, Mette Madsen, Adam Kilkenney, Brittany Gregory, Erik I Christensen, Henrik Vorum, Peter Hojrup, Alejandro A Schaffer, Ewen F Kirkness, Stephan M Tanner, Albert de la Chapelle, Urs Giger, Soren K Moestrup, and John C Fyfe*
Department of Microbiology & Molecular Genetics, College of Veterinary Medicine, Michigan State University, East Lansing, MI, USA
Department of Medical Biochemistry, University of Aarhus, Aarhus, Denmark
Department of Cell Biology, Institute of Anatomy, University of Aarhus, Aarhus, Denmark
Department of Biochemistry and Molecular Biology, Odense University, Odense, Denmark
National Center for Biotechnology Information, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA
The Institute for Genomic Research, Rockville, MD, USA
Human Cancer Genetics Program, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
Section of Medical Genetics, Veterinary Hospital of the University of Pennsylvania, Philadelphia, PA, USA
* Corresponding author; email: fyfe{at}cvm.msu.edu.
Amnionless (AMN) and cubilin gene products appear to be essential functional subunits of an endocytic receptor called cubam. Mutation of either gene causes autosomal recessive Imerslund-Grasbeck syndrome (I-GS, OMIM #261100) in humans, a disorder characterized by selective intestinal malabsorption of cobalamin (vitamin B12) and urinary loss of several specific low molecular weight proteins. Vital insight into the molecular pathology of I-GS has been obtained from studies of dogs with a similar syndrome. In this work, we show that I-GS segregates in a large canine kindred due to an in-frame deletion of 33 nucleotides in exon 10 of AMN. In a second, unrelated I-GS kindred, affected dogs exhibit a homozygous substitution in the AMN translation initiation codon. Studies in vivo demonstrated that both mutations abrogate AMN expression and block cubilin processing and targeting to the apical membrane. The essential features of AMN dysfunction observed in vivo are recapitulated in a heterologous cell transfection system, thus validating the system for analysis of AMN-cubilin interactions. Characterization of canine AMN mutations that cause I-GS establishes the canine model as an orthologue of the human disorder well suited to studies of AMN function and co-evolution with cubilin.
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