Inversions disrupting the factor VIII gene are a common cause of severe haemophilia A.
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.
Lakich
D
D
Howard Hughes Medical Institute, University of California, San Francisco 94143-0724.
Kazazian
H H
HH
Antonarakis
S E
SE
Gitschier
J
J
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
D017931:DNA Primers; D005169:Factor VIII