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DOI: 10.1055/s-0037-1612988
Novel Factor V C2-Domain Mutation (R2074H) in Two Families with Factor V Deficiency and Bleeding
Publikationsverlauf
Received
09. Juli 2001
Accepted after resubmission
21. November 2001
Publikationsdatum:
13. Dezember 2017 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/200202/lookinside/thumbnails/10-1055-s-0037-1612988-1.jpg)
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.
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