title: Mutation analysis in 51 patients with haemophilia A: report of 10 novel mutations and correlations between genotype and clinical phenotype.
abstract: We report the results of genetic analysis on a series of 51 patients attending this Haemophilia Comprehensive Care Centre. The most common cause of severe haemophilia A--the factor VIII intron 22 inversion was detected in eight families and the factor VIII intron 1 inversion in three families. Mutation analysis was carried out on the remaining patients by nucleotide sequencing of genomic DNA after screening with conformation-sensitive gel electrophoresis (CSGE) or denaturing high-performance liquid chromatography (dHPLC). A total of 27 different FVIII non-inversion mutations were detected. Severe haemophilia was associated with 12 null mutations (six nonsense, six frameshift) and four missense mutations. A further 11 different missense mutations were associated with moderate or mild disease. To our knowledge, six null mutations [1950del 4(tttg), 3270-75insA, 4416del 10, 6735-38delA, W1029X, Y1792X] and four missense mutations (E1682K, M1947V, P2048L, P2143L) have not been previously published. Each novel missense mutation occurred at a highly conserved residue, no other candidate mutation was detected on screening the entire coding region of the FVIII gene and they were not detected in a screen of individuals without haemophilia A. The genotype-phenotype correlations of the FVIII mutations detected will be discussed.
authors.affiliation: Department of Clinical Chemistry and Haematology, University Hospital, Queens Medical Centre, Nottingham, UK. marian.hill@nottingham.ac.uk
authors.forename: M
authors.initials: M
authors.lastname: Hill
authors.forename: S
authors.initials: S
authors.lastname: Deam
authors.forename: B
authors.initials: B
authors.lastname: Gordon
authors.forename: G
authors.initials: G
authors.lastname: Dolan
mesh_terms: D001483:Base Sequence; D018389:Codon, Nonsense / Q000235:genetics; D004247:DNA / Q000235:genetics; D004252:DNA Mutational Analysis / Q000379:methods; D005169:Factor VIII / Q000037:antagonists & inhibitors / Q000235:genetics; D016368:Frameshift Mutation / Q000235:genetics; D005838:Genotype; D006467:Hemophilia A / Q000235:genetics*; D006801:Humans; D047668:Inteins / Q000235:genetics; D008297:Male; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D010641:Phenotype
chemical_list: D018389:Codon, Nonsense; D005169:Factor VIII; D004247:DNA