title: Haemophilia A mutations in the UK: results of screening one-third of the population.
abstract: One-third of the UK haemophilia A population was screened to establish a national database of mutations and pedigrees and advance knowledge of the disease. The following mutations were found: 131 intron 22- and 13 intron1-breaking inversions; 11 gross deletions and an insertion; 65 frameshifts; three in-frame deletions and one insertion; 46 nonsense; 30 intronic mutations affecting splice sites and four generating new sites; 469 non-synonymous mutations due to 203 different base substitutions of which four affected, and nine were predicted to affect, splicing; three promoter mutations; two synonymous exon 14 mutations possibly affecting splicing; two VWF mutations. Of the above mutations, 176 are not listed in the Haemophilia A Mutation, Structure, Test and Resource Site (HAMSTeRS). Four gross deletions arose by non-homologous end-joining; we detected unexpected splicing in some mutations; substitution of amino acids conserved for less than 90 million years are rare; the risk of developing inhibitors for patients with nonsense mutations is greater when the stop codon is in the 3' half of the mRNA; changes likely to generate splice sites causing frameshifts are over-represented among non-synonymous mutations associated with inhibitors; our data and those in HAMSTeRS enabled the size of the spectrum of specific mutations causing the disease to be estimated and to determine how much of it is known.
authors.affiliation: Department of Medical & Molecular Genetics, Kings College London, Guy's Hospital, London, UK.
authors.forename: P M
authors.initials: PM
authors.lastname: Green
authors.forename: R D
authors.initials: RD
authors.lastname: Bagnall
authors.forename: N H
authors.initials: NH
authors.lastname: Waseem
authors.forename: F
authors.initials: F
authors.lastname: Giannelli
mesh_terms: D017398:Alternative Splicing; D007446:Chromosome Inversion; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D030541:Databases, Genetic; D005260:Female; D016368:Frameshift Mutation; D017353:Gene Deletion; D006467:Hemophilia A / Q000235:genetics*; D006801:Humans; D007438:Introns / Q000235:genetics; D008297:Male; D008403:Mass Screening; D009154:Mutation; D020125:Mutation, Missense; D015995:Prevalence; D011401:Promoter Regions, Genetic / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D006113:United Kingdom
chemical_list: D018389:Codon, Nonsense