PMID: 2494175Mar 15, 1989Paper

A moderate form of hemophilia B is caused by a novel mutation in the protease domain of factor IXVancouver.

The Journal of Biological Chemistry
V A GeddesR T MacGillivray

Abstract

A genomic phage library was constructed using lymphocyte DNA from a patient with cross-reacting material-positive, moderately severe hemophilia B. The library was screened by using a full-length factor IX cDNA as a hybridization probe. DNA sequence analysis of the factor IX exons and intron/exon junctions revealed a single point mutation at nucleotide 31,311 of the gene. This mutation occurs in the protease domain of factor IXa and changes the codon for isoleucine 397 (ATA) to a threonine codon (ACA). The resulting abnormal protein has been named factor IXVancouver. Factor IXVancouver was isolated from the patient's plasma by barium citrate adsorption, affinity chromatography on a Ca2+-dependent antibody bound to agarose, and anion-exchange chromatography. On gel electrophoresis, the purified protein exhibited a normal molecular weight and a normal pattern of activation cleavages with bovine factor XIa. Kinetic studies on the purified protein indicated that the Km of factor IXaVancouver for human factor X was 3.4 times higher than that of normal factor IXa. The kcat of factor IXaVancouver was 12.5% of the kcat of normal factor IXa. Structural models of the protease domain of human factor IXa and of factor IXaVancouver were cons...Continue Reading

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