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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
Renata Kozyraki,
Mette Kristiansen,
Asli Silahtaroglu,
Claus Hansen,
Christian Jacobsen,
Niels Tommerup,
Pierre J. Verroust, and
Søren K. Moestrup
From the Institut National de la Santé et de la
Recherche Médicale, U489, Hôpital Tenon, Paris, France; the
Department of Medical Biochemistry, University of Aarhus, Aarhus,
Denmark; and the Department of Medical Genetics, Institute of
Medical Biochemistry and Genetics, The Panum Institute, University of
Copenhagen, Copenhagen, Denmark.
Uptake of vitamin B12 (cyanocobalamin) is facilitated by
the cobalamin-binder gastric intrinsic factor (IF), which recognizes a
460-kD receptor, cubilin, present in the epithelium of
intestine and kidney. Surface plasmon resonance analysis of
ligand-affinity-purified human cubilin demonstrated a high-affinity
calcium- and cobalamin-dependent binding of IF-cobalamin. Complete cDNA
cloning of the human receptor showed a 3597 amino acid peripheral
membrane protein with 69% identity to rat cubilin. Amino-terminal
sequencing of the receptor indicates that the cDNA sequence encodes a
precursor protein undergoing proteolytic processing due to cleavage at
a recognition site
(Arg7-Glu8-Lys9-Arg)
for the trans-Golgi proteinase furin. Using fluorescence in situ
hybridization, radiation hybrid mapping, and screening of YAC clones,
the human cubilin gene was mapped between the markers D10S1661 and
WI-5445 on the short arm of chromosome 10. This is within the autosomal
recessive megaloblastic anemia (MGA1) 6-cM region harboring the unknown
recessive-gene locus of juvenile megaloblastic anemia caused by
intestinal malabsorption of cobalamin (Imerslund-Gräsbeck's
disease). In conclusion, the present molecular and genetic information
on human cubilin now provides circumstantial evidence that an impaired
synthesis, processing, or ligand binding of cubilin is the molecular
background of this hereditary form of megaloblastic anemia.
Blood, Vol. 91 No. 10 (May 15), 1998:
pp. 3593-3600
© 1998 by The American Society of Hematology.
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