title: Novel factor V C2-domain mutation (R2074H) in two families with factor V deficiency and bleeding.
abstract: 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.
authors.affiliation: Department of Pathology, Stanford University School of Medicine, CA 94305, USA.
authors.forename: I
authors.initials: I
authors.lastname: Schrijver
authors.forename: R
authors.initials: R
authors.lastname: Houissa-Kastally
authors.forename: C D
authors.initials: CD
authors.lastname: Jones
authors.forename: K C
authors.initials: KC
authors.lastname: Garcia
authors.forename: J L
authors.initials: JL
authors.lastname: Zehnder
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D003241:Consanguinity; D004200:Diseases in Twins; D005165:Factor V / Q000737:chemistry / Q000235:genetics*; D005166:Factor V Deficiency / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D017354:Point Mutation; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D014416:Tunisia
chemical_list: D005165:Factor V