TY - JOUR
T1 - Factor VIII gene inversions causing severe hemophilia A originate almost exclusively in male germ cells
AU - Rosslter, Judith Pratt
AU - Young, Michele
AU - Kimberland, Michelle L.
AU - Hutter, Pierre
AU - Ketterling, Rhett P.
AU - Gitschier, Jane
AU - Horst, Jürgen
AU - Morris, Michael A.
AU - Schaid, Daniel J.
AU - De Moerloose, Phillppe
AU - Sommer, Steve S.
AU - Kazazian, Haig H.
AU - Antonarakis, Styllanos E.
N1 - Funding Information:
We thank J.Phillips, C.Kasper, R.Janco, L.Kasch, C.Talbot, D.Jenkins, C.Paynton, C.Dutton, A.Schonbomer, A.Eigel and C.Boehm for providing patient material and assistance in various phases of the work. This work was supported by grants from the NIH to 1) HHK and SEA, 2) SSS, 3) JG. SEA was also supported by a grant from the Swiss National Science Foundation. RPK is a Howard Hughes Medical Institute medical student research training fellow.
PY - 1994/7
Y1 - 1994/7
N2 - 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.
AB - 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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U2 - 10.1093/hmg/3.7.1035
DO - 10.1093/hmg/3.7.1035
M3 - Article
C2 - 7981669
AN - SCOPUS:0028180964
SN - 0964-6906
VL - 3
SP - 1035
EP - 1039
JO - Human molecular genetics
JF - Human molecular genetics
IS - 7
ER -