Factor VIII (FVIII) gene mutations in 120 patients with hemophilia A: detection of 26 novel mutations and correlation with FVIII inhibitor development

Abstract

Summary. Background: As the publication of the sequence of the factor VIII gene (FVIII) in 1984, a large number of mutations that cause hemophilia A (HA) have been identified. Thanks to the advances in the detection of mutations, it is now possible to identify a putative FVIII sequence alteration in the vast majority of patients with HA. Objectives: Our main objective was to report on the spectrum of FVIII mutations and their distribution throughout the gene in 120 patients with HA. Methods: Screening of FVIII mutations was performed using direct sequencing. Newly described missense mutations were further studied by molecular modeling. Results: A total of 47 different HA causative FVIII mutations have been identified, 26 of which are described for the first time. These novel mutations include 14 missense and six nonsense mutations, two small deletions, one large deletion and three splice-site mutations. We further investigated the development of FVIIIspecific inhibitors in all patients with HA. We found that four novel mutations (Ser882X, Tyr1786Ser, Ala2218Thr and a splice-site defect in intron 22) were associated with inhibitor development. Conclusion: These data extend our insight into the mechanisms by which novel amino acid substitutions may lead to HA, and how HA patient genotypes influence the risk of FVIII inhibitor development.

The Italian AICE-Genetics hemophilia A database: results and correlation with clinical phenotype

“…The types of mutations found were in agreement with results reported in other settings (Table 2). [15][16][17][18][19][20][21][22][23][24] As expected, most of patients with severe HA carry a molecular defect predicting a null allele (large deletion, inversion, nonsense, and insertion/deletion mutations), whereas missense mutations have been found in the majority of patients with moderate (68%) and mild HA (80%).…”

Mutation Screening of the Factor VIII Gene in Hemophilia A in Saudi Arabia: Two Novel Mutations and Genotype-Phenotype Correlation

“…Genetic mutations in factor VIII cause deregulation of this protein leading to bleeding disorders [15][16][17][18][19]. Defects in factor VIII gene includes deletions, large DNA inversions, nonsense mutations, ins/ del-frame shifts, splice variants and a large number of missense point mutations, all of which can cause defects in the expression, secretion, and/or half-life of factor VIII protein in circulation [20][21][22][23][24][25].…”

“…Several studies are available in literature describing the mutations in factor VIII gene, from many ethnic groups and different populations [16,17,25,29,30]. Recently, some reports were published from Middle Eastern countries also describing factor VIII gene mutations [31][32][33][34].…”

Identification of Four Novel Factor VIII Gene Mutations and Protein Structure Analysis using Molecular Dynamic Simulation

“…A total of 1388 missense/ nonsense, 377 small deletions, 156 splicing, 117 small insertions, 27 small indels, 213 gross deletions, 26 gross insertions, 12 complex rearrangements, and four regulatory mutations have so far been detected [3,7]. Several studies have been conducted describing the mutations in the Western populations [8][9][10][11][12], however, the spectrum and nature of common mutations carrying haemophilia A in Arab population is still lacking investigation. Specifically the data available for frequent mutations is insufficient among Saudi population.…”