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

Jerry B. Lefkowitz; Rachelle Nuss; Tara Haver; Linda Jacobson; Arthur R. Thompson; Marilyn Manco-Johnson

doi:10.1055/s-0037-1616144

Thrombosis and Haemostasis, Table of Contents

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

¹Department of Pathology

,

Rachelle Nuss

²Department of Pediatrics, University of Colorado School of Medicine, Denver, CO

,

Tara Haver

¹Department of Pathology

,

Linda Jacobson

²Department of Pediatrics, University of Colorado School of Medicine, Denver, CO

,

Arthur R. Thompson

³Puget Sound Blood Center, and the University of Washington, Seattle, WA, USA

,

Marilyn Manco-Johnson

²Department of Pediatrics, University of Colorado School of Medicine, Denver, CO

› Author Affiliations

Abstract

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 k_cat, but a significant difference when factor VIIIa (FVIIIa) was included in the reaction. Using kinetic assays to infer the K_d of FIXa for FVIIIa, normal FIXa had a K_d 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

Full Text

References

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