title: Characterisation of 96 mutations in 128 unrelated severe haemophilia A patients from France. Description of 62 novel mutations.
abstract: Direct sequencing of the coding region of factor VIII (F8) gene was used to determine the mutations responsible for severe haemophilia A (FVIII<1%) in 128 unrelated haemophiliacs A, negative for intron 22 and intron 1 inversions. A mutation was found in 122/128 patients (95%). Ninety-six distinct mutations were identified in this cohort, 62 of these are novel. They consisted of deletions (7 large and 24 small deletions), insertions (n = 9), associations of insertion/deletion (n = 2), association of deletion/substitution (n = 1), and single nucleotide substitutions (53 point mutations consisting of 31 missense, 20 nonsense, and 2 splicing mutations). Twenty-two patients had developed inhibitors, and among this subgroup 3 large deletions, 6 frameshift, 9 nonsense and 4 missense mutations were detected. For 6 patients, among which one developed an anti-FVIII inhibitor, no mutations were detected in the coding and splicing regions of factor VIII gene. Different approaches of molecular modelling were performed in addition to familial linkage analysis to determine the pathophysiological responsibility of these novel missense mutations.
authors.affiliation: Laboratoire d'hémostase, Hopital Edouard Herriot, 69437 Lyon Cedex 03, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Vinciguerra
authors.forename: Christophe
authors.initials: C
authors.lastname: Zawadzki
authors.forename: Yesim
authors.initials: Y
authors.lastname: Dargaud
authors.forename: Gilles
authors.initials: G
authors.lastname: Pernod
authors.forename: Claire
authors.initials: C
authors.lastname: Berger
authors.forename: Christophe
authors.initials: C
authors.lastname: Nougier
authors.forename: Claude
authors.initials: C
authors.lastname: Négrier
mesh_terms: D001780:Blood Coagulation Tests; D015331:Cohort Studies; D005169:Factor VIII / Q000235:genetics*; D005260:Female; D005602:France; D017353:Gene Deletion; D008040:Genetic Linkage; D006467:Hemophilia A / Q000235:genetics*; D006801:Humans; D007438:Introns; D008297:Male; D009154:Mutation; D017354:Point Mutation; D017422:Sequence Analysis, DNA / Q000379:methods
chemical_list: D005169:Factor VIII