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

Judith Pratt Rosslter, Michele Young, Michelle L. Kimberland, Pierre Hutter, Rhett P. Ketterling, Jane Gitschier, Jürgen Horst, Michael A. Morris, Daniel J. Schaid, Phillppe De Moerloose, Steve S. Sommer, Haig H. Kazazian, Styllanos E. Antonarakis

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132 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1035-1039
Number of pages5
JournalHuman molecular genetics
Issue number7
StatePublished - Jul 1 1994


ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Rosslter, J. P., Young, M., Kimberland, M. L., Hutter, P., Ketterling, R. P., Gitschier, J., Horst, J., Morris, M. A., Schaid, D. J., De Moerloose, P., Sommer, S. S., Kazazian, H. H., & Antonarakis, S. E. (1994). Factor VIII gene inversions causing severe hemophilia A originate almost exclusively in male germ cells. Human molecular genetics, 3(7), 1035-1039. https://doi.org/10.1093/hmg/3.7.1035