title: The identification and classification of 41 novel mutations in the factor VIII gene (F8C).
abstract: Hemophilia A is a bleeding disorder caused by a quantitative or qualitative deficiency in the coagulation factor VIII. Causative mutations are heterogeneous in nature and are distributed throughout the FVIII gene. With the exception of mutations that result in prematurely truncated protein, it has proved difficult to correlate mutation type/amino acid substitution with severity of disease. We have identified 81 mutations in 96 unrelated patients, all of whom have typed negative for the common IVS-22 inversion mutation. Forty-one of these mutations are not recorded on F8C gene mutation databases. We have analyzed these 41 mutations with regard to location, whether or not each is a cross-species conserved region, and type of substitution and correlated this information with the clinical severity of the disease. Our findings support the view that the phenotypic result of a mutation in the FVIII gene correlates more with the position of the amino acid change within the 3D structure of the protein than with the actual nature of the alteration.
authors.affiliation: The Haemophilia Reference Centre, Centre for Thrombosis and Haemostasis, St Thomas' Hospital, Lambeth Palace Road, London, UK. jacqueline.cutler@gstt.sthames.nhs.uk
authors.forename: J A
authors.initials: JA
authors.lastname: Cutler
authors.forename: M J
authors.initials: MJ
authors.lastname: Mitchell
authors.forename: M P
authors.initials: MP
authors.lastname: Smith
authors.forename: G F
authors.initials: GF
authors.lastname: Savidge
mesh_terms: D000818:Animals; D018389:Codon, Nonsense / Q000235:genetics; D004252:DNA Mutational Analysis / Q000379:methods; D004285:Dogs; D005169:Factor VIII / Q000235:genetics*; D005260:Female; D005838:Genotype; D006467:Hemophilia A / Q000097:blood / Q000235:genetics; D006801:Humans; D051379:Mice; D016254:Mutagenesis, Insertional / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D010641:Phenotype; D018807:Polymorphism, Single-Stranded Conformational; D022821:RNA Splice Sites / Q000235:genetics; D017384:Sequence Deletion / Q000235:genetics
chemical_list: D018389:Codon, Nonsense; D022821:RNA Splice Sites; D005169:Factor VIII