title: Inversions disrupting the factor VIII gene are a common cause of severe haemophilia A.
abstract: Mutations in the factor VIII gene have been discovered for barely more than half of the examined cases of severe haemophilia A. To account for the unidentified mutations, we propose a model based on the possibility of recombination between homologous sequences located in intron 22 and upstream of the factor VIII gene. Such a recombination would lead to an inversion of all intervening DNA and a disruption of the gene. We present evidence to support this model and describe a Southern blot assay that detects the inversion. These findings should be valuable for genetic prediction of haemophilia A in approximately 45% of families with severe disease.
authors.affiliation: Howard Hughes Medical Institute, University of California, San Francisco 94143-0724.
authors.forename: D
authors.initials: D
authors.lastname: Lakich
authors.forename: H H
authors.initials: HH
authors.lastname: Kazazian
authors.forename: S E
authors.initials: SE
authors.lastname: Antonarakis
authors.forename: J
authors.initials: J
authors.lastname: Gitschier
mesh_terms: D001483:Base Sequence; D015139:Blotting, Southern; D002461:Cell Line, Transformed; D007446:Chromosome Inversion; D017931:DNA Primers; D005091:Exons; D005169:Factor VIII / Q000235:genetics*; D006467:Hemophilia A / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D016133:Polymerase Chain Reaction; D011995:Recombination, Genetic
chemical_list: D017931:DNA Primers; D005169:Factor VIII