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Cubilin P1297L mutation associated with hereditary megaloblastic anemia 1 causes impaired recognition of intrinsic factor-vitamin B(12) by cubilin.

Blood | Jul 15, 2000

Megaloblastic anemia 1 (MGA1) is an autosomal recessive disorder caused by the selective intestinal malabsorption of intrinsic factor (IF) and vitamin B(12)/cobalamin (Cbl) in complex. Most Finnish patients with MGA1 carry the disease-specific P1297L mutation (FM1) in the IF-B(12) 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 K(d) 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 degrees 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. (Blood. 2000;96:405-409)

Pubmed ID: 10887099 RIS Download

Mesh terms: Anemia, Megaloblastic | Binding Sites | Cloning, Molecular | Gene Expression | Humans | Intrinsic Factor | Membrane Glycoproteins | Mutagenesis, Site-Directed | Mutation | Polymerase Chain Reaction | Receptors, Cell Surface | Structure-Activity Relationship | Surface Plasmon Resonance | Transfection | Vitamin B 12

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