Factor IX Denver, ASN 346→ASP Mutation Resulting in a Dysfunctional Protein with Defective Factor VIIIa Interaction
Copyright policy )Factor IX Denver, ASN 346→ASP Mutation Resulting in a Dysfunctional Protein with Defective Factor VIIIa Interaction
SummaryHemophilia B is a sex-linked recessive bleeding disorder characterized by the presence of either a decreased amount of normal factor IX (FIX) or the presence of a dysfunctional FIX. We have identified a unique mutation in a family with mild hemophilia B. DNA analysis of family members revealed a single base transition in the 8th exon of the FIX gene predicting an amino acid change of Asn 346→Asp in the catalytic domain. The FIX variant, named FIX Denver, was purified from proband plasma. Kinetic studies of factor X (FX) interactions with normal FIXa or FIXa Denver and phospholipid (PL) showed little difference in kcat, but a significant difference when factor VIIIa (FVIIIa) was included in the reaction. Using kinetic assays to infer the Kd of FIXa for FVIIIa, normal FIXa had a Kd of 0.095 nM while that of FIXa Denver was 9.85 nM. The major defect caused by this point mutation is a marked decrease in the affinity of FIXa Denver for factor VIIIa.
- University of Colorado Denver United States
- University of Colorado Cancer Center United States
Adult, Male, DNA Mutational Analysis, Mutation, Missense, Hemorrhage, Phosphatidylserines, Hemophilia B, Thromboplastin, Factor IX, Humans, Point Mutation, Factor VIIIa, Neoplasm Proteins, Cysteine Endopeptidases, Kinetics, Amino Acid Substitution, Factor X, Liposomes, Phosphatidylcholines, Blood Coagulation Tests
Adult, Male, DNA Mutational Analysis, Mutation, Missense, Hemorrhage, Phosphatidylserines, Hemophilia B, Thromboplastin, Factor IX, Humans, Point Mutation, Factor VIIIa, Neoplasm Proteins, Cysteine Endopeptidases, Kinetics, Amino Acid Substitution, Factor X, Liposomes, Phosphatidylcholines, Blood Coagulation Tests
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