Characterisation of 96 mutations in 128 unrelated severe haemophilia A patients from France

Christine Vinciguerra; Christophe Zawadzki; Yesim Dargaud; Gilles Pernod; Claire Berger; Christophe Nougier; Claude Négrier

doi:10.1160/TH05-05-0379

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2006; 95(04): 593-599
DOI: 10.1160/TH05-05-0379

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

Authors

Christine Vinciguerra

¹Laboratoire d’hémostase, Hopital Edouard Herriot, Lyon, France

²EA 3735, Université Claude Bernard, Lyon I, France
Christophe Zawadzki

³Laboratoire d’hématologie, Inserm ERI9, EA2693, Université Lille II, CHRU Lille, France
Yesim Dargaud

¹Laboratoire d’hémostase, Hopital Edouard Herriot, Lyon, France
Gilles Pernod

⁴Laboratoire d’hématologie, Centre Hospitalo-Universitaire de Grenoble, France
Claire Berger

⁵Service de pédiatrie, Centre Hospitalo-Universitaire de St. Etienne, France
Christophe Nougier

¹Laboratoire d’hémostase, Hopital Edouard Herriot, Lyon, France
Claude Négrier

¹Laboratoire d’hémostase, Hopital Edouard Herriot, Lyon, France

²EA 3735, Université Claude Bernard, Lyon I, France

⁶Centre régional de traitement de l’hémophilie, Hopital Edouard Herriot, Lyon, France

Abstract

Summary

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.

Keywords

Haemophilia A/B - gene mutations - inherited coagulation disorders

Full Text

References

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