Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH
Characterisation of 96 mutations in 128 unrelated severe haemophilia A patients from France
Description of 62 novel mutations
Christine Vinciguerra
1
Laboratoire d’hémostase, Hopital Edouard Herriot, Lyon, France
2
EA 3735, Université Claude Bernard, Lyon I, France
,
Christophe Zawadzki
3
Laboratoire d’hématologie, Inserm ERI9, EA2693, Université Lille II, CHRU Lille, France
,
Yesim Dargaud
1
Laboratoire d’hémostase, Hopital Edouard Herriot, Lyon, France
,
Gilles Pernod
4
Laboratoire d’hématologie, Centre Hospitalo-Universitaire de Grenoble, France
,
Claire Berger
5
Service de pédiatrie, Centre Hospitalo-Universitaire de St. Etienne, France
,
Christophe Nougier
1
Laboratoire d’hémostase, Hopital Edouard Herriot, Lyon, France
,
Claude Négrier
1
Laboratoire d’hémostase, Hopital Edouard Herriot, Lyon, France
2
EA 3735, Université Claude Bernard, Lyon I, France
6
Centre régional de traitement de l’hémophilie, Hopital Edouard Herriot, Lyon, France
› Author AffiliationsFinancial support: This work was supported by grants from Ministère de la Santé (PHRC), Hospices Civils de Lyon, INSERM and Wyeth-Genetics Institute.
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. For6 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.
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