Novel Factor V C2-Domain Mutation (R2074H) in Two Families with Factor V Deficiency and Bleeding

I. Schrijver; R. Houissa-Kastally; C. D. Jones; K. C. Garcia; J. L. Zehnder

doi:10.1055/s-0037-1612988

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2002; 87(02): 294-299
DOI: 10.1055/s-0037-1612988

Letters to the Editor

Schattauer GmbH

Novel Factor V C2-Domain Mutation (R2074H) in Two Families with Factor V Deficiency and Bleeding

I. Schrijver

¹Department of Pathology, and the Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA; and the Clinical Biology Laboratory, Habib Thameur Hospital, Tunis, Tunisia

,

R. Houissa-Kastally

¹Department of Pathology, and the Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA; and the Clinical Biology Laboratory, Habib Thameur Hospital, Tunis, Tunisia

,

C. D. Jones

¹Department of Pathology, and the Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA; and the Clinical Biology Laboratory, Habib Thameur Hospital, Tunis, Tunisia

,

K. C. Garcia

¹Department of Pathology, and the Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA; and the Clinical Biology Laboratory, Habib Thameur Hospital, Tunis, Tunisia

,

J. L. Zehnder

¹Department of Pathology, and the Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA; and the Clinical Biology Laboratory, Habib Thameur Hospital, Tunis, Tunisia

› Institutsangaben

Abstract

Summary

The molecular basis of Factor V deficiency has been defined in few patients only. We report a homozygous nucleotide change (G6395A) in two Tunisian probands with Factor V deficiency and bleeding episodes. This substitution results in the replacement of an arginine (R) by a histidine (H) in amino acid position 2074, located in the Factor V C2-domain. Mutations in this protein domain have not previously been described. Several lines of evidence support that this sequence variant is indeed disease causing: 1) Crystal structures of Factor V and molecular C2-domain modeling studies of H2074 suggest that the conserved R2074 is required for correct folding; 2) Structure-function studies of selective Factor V mutants (R2074A) demonstrate the importance of R2074 for structural stability of the Factor V C2-domain and for cofactor activity (1); 3) In Factor VIII, point mutations in codon 2209, which corresponds to position 2074 in Factor V, cause hemophilia A.

Keywords

Factor V deficiency - parahemophilia - inherited coagulation disorders - Factor V - bleeding

Volltext

Referenzen

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