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Blood, Vol. 96 No. 2 (July 15), 2000:
pp. 405-409
PLENARY PAPER
Cubilin P1297L mutation associated with hereditary megaloblastic
anemia 1 causes impaired recognition of intrinsic factor-vitamin
B12 by cubilin
Mette Kristiansen,
Maria Aminoff,
Christian Jacobsen,
Albert de la Chapelle,
Ralf Krahe,
Pierre J. Verroust, and
Søren K. Moestrup
From the Department of Medical Biochemistry, University of Aarhus,
Aarhus, Denmark; the Division of Human Cancer Genetics, Departments of
Molecular Virology, Immunology and Medical Genetics, Comprehensive
Cancer Center, Ohio State University, Columbus, OH; the
Folkhälsan Institute of Genetics, University of Helsinki,
Finland; and Inserm U538, CHU St Antoine, Paris, France.
Megaloblastic anemia 1 (MGA1) is an autosomal recessive disorder
caused by the selective intestinal malabsorption of intrinsic factor
(IF) and vitamin B12/cobalamin (Cbl) in complex. Most
Finnish patients with MGA1 carry the disease-specific P1297L mutation (FM1) in the IF-B12 receptor, cubilin. By site-directed
mutagenesis, mammalian expression, and functional comparison of the
purified wild-type and FM1 mutant forms of the IF-Cbl-binding cubilin
region (CUB domains 5-8, amino acid 928-1386), we have investigated the functional implications of the P1297L mutation. Surface plasmon resonance analysis revealed that the P1297L substitution specifically increases the Kd for IF-Cbl binding several-fold,
largely by decreasing the association rate constant. In agreement with
the binding data, the wild-type protein, but not the FM1 mutant
protein, potently inhibits 37°C uptake of iodine 125-IF-Cbl in
cubilin-expressing epithelial cells. In conclusion, the data presented
show a substantial loss in affinity of the FM1 mutant form of the
IF-Cbl binding region of cubilin. This now explains the malabsorption
of Cbl and Cbl-dependent anemia in MGA1 patients with the FM1 mutation.
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