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© 1994 Oxford University Press

RESEARCH-ARTICLE

Factor VIII gene inversions causing severe hemophilia A originate almost exclusively in male germ cells

Judith Pratt Rosslter, Michele Young1, Michelle L. Kimberland, Pierre Hutter1, Rhett P. Ketterling2, Jane Gitschier3, Jürgen Horst4, Michael A. Morris1, Daniel J. Schaid5, Phillppe de Moerloose6, Steve S. Sommer2, Haig H. Kazazian, Jr.* and Styllanos E. Antonarakis1,*

Center for Medical Genetics, The Johns Hopkins University School of Medicine 600 N.Wolfe Street, Baltimore, MD 21287, USA 1Division of Medical Genetics, University of Geneva Medical School &Cantonal Hospital Geneva, Switzerland 2Department of Biochemistry and Molecular Biology, Mayo Clinic/Foundation Rochester, MN 3Howard Hughes Medical Institute and Department of Medicine, University of California San Francisco, CA, USA 4Institut fur Humangenetik der UniSwitzerland Munster, Germany 5Section of Biostatistics, Department of Health Sciences Research, Mayo Clinic/Foundation Rochester, MN, USA 6Hemostasis and Thrombosis Unit, Cantonal Hospital Geneva, Switzerland

*To whom correspondence should be addressed

Received March 22, 1994; Revised May 13, 1994; Accepted May 13, 1994

The factor VIII gene, which is defective In hemophilia A, is located in the last megabase of the long arm of the X chromosome. Inversions due to intrachromosomal homologous recombination between mispaired copies of gene A located within intron 22 of the gene and about 500 kb telomeric to it account for nearly half of all cases of severe hemophilia A. We hypothesized that pairing of Xq with its homolog inhibits the Inversion process, and that, therefore, the event originates predominantly in male germ cells. In all 20 informative cases In which the inversion originated in a maternal grandparent, DNA polymorphism analysis determined that it occurred in the male germline. In addition, all but one of 50 mothers of sporadic cases due to an Inversion were carriers. Thus, these data support the hypothesis and Indicate that factor VIII gene inversions leading to severe hemophilia A occur almost exclusively In male germ cells.


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