title: Spectrum of molecular defects and mutation detection rate in patients with severe hemophilia A.
abstract: Hemophilia A is the most frequently occurring X-linked bleeding disorder, affecting one to two out of 10,000 males worldwide. Various types of mutations in the F8 gene are causative for this condition. It is well known that the most common mutation in severely affected patients is the intron 22 inversion, which accounts for about 45% of cases with F8 residual activity of less than 1%. Therefore, the aim of the present study was to determine the spectrum and distribution of mutations in the F8 gene in a large group of patients with severe hemophilia A who previously tested negative for the common intron 22 inversion. Here we report on a mutation analysis of 86 patients collected under the above-mentioned criterion. The pathogenic molecular defect was identified in all patients, and thus our detection rate was virtually 100%. Thirty-four of the identified mutations are described for the first time. The newly detected amino acid substitutions were scored for potential gross or local conformational changes and influence on molecular stability for every single F8 domain with available structures, using homology modeling.
authors.affiliation: Institut für Humangenetik, UKM, Münster, Germany.
authors.forename: Nadja
authors.initials: N
authors.lastname: Bogdanova
authors.forename: Arseni
authors.initials: A
authors.lastname: Markoff
authors.forename: Hartmut
authors.initials: H
authors.lastname: Pollmann
authors.forename: Ulrike
authors.initials: U
authors.lastname: Nowak-Göttl
authors.forename: Roswith
authors.initials: R
authors.lastname: Eisert
authors.forename: Cornelia
authors.initials: C
authors.lastname: Wermes
authors.forename: Albena
authors.initials: A
authors.lastname: Todorova
authors.forename: Antonin
authors.initials: A
authors.lastname: Eigel
authors.forename: Bernd
authors.initials: B
authors.lastname: Dworniczak
authors.forename: Jürgen
authors.initials: J
authors.lastname: Horst
mesh_terms: D041321:Chromosomes, Human, X; D004252:DNA Mutational Analysis; D005169:Factor VIII / Q000235:genetics*; D005260:Female; D006467:Hemophilia A / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D007438:Introns; D008297:Male; D008957:Models, Genetic; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D009154:Mutation; D011110:Polymorphism, Genetic
chemical_list: D005169:Factor VIII