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Thromb Haemost 2001; 86(03): 862-870
DOI: 10.1055/s-0037-1616144
Review Articles
Schattauer GmbH

Factor IX Denver, ASN 346→ASP Mutation Resulting in a Dysfunctional Protein with Defective Factor VIIIa Interaction

Jerry B. Lefkowitz
1   Department of Pathology
,
Rachelle Nuss
2   Department of Pediatrics, University of Colorado School of Medicine, Denver, CO
,
Tara Haver
1   Department of Pathology
,
Linda Jacobson
2   Department of Pediatrics, University of Colorado School of Medicine, Denver, CO
,
Arthur R. Thompson
3   Puget Sound Blood Center, and the University of Washington, Seattle, WA, USA
,
Marilyn Manco-Johnson
2   Department of Pediatrics, University of Colorado School of Medicine, Denver, CO
› Author Affiliations
Further Information

Publication History

Received 19 October 2000

Accepted after revision 25 April 2001

Publication Date:
14 December 2017 (online)

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Summary

Hemophilia 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.

Keywords

Factor IX - factor VIII - factor X - hemophilia B - hemorrhage
 

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