Molecular defects in hemophilia A: identification and characterization of mutations in the factor VIII gene and family analysis.
Hemophilia A is an X-linked bleeding disorder caused by a deficiency or abnormality of factor VIII, affecting approximately 1 male in 10,000. A subgroup of the patients develops inhibitors against factor VIII during substitution therapy. Because a considerable percentage of all cases is thought to result from de novo mutations, it is likely that many different molecular lesions lead to hemophilia A. In order to understand the molecular basis of this disorder, we examined 160 patients with different clinical features using factor VIII gene probes. We could identify six different deletions and seven nonsense mutations within the factor VIII gene. Family analysis revealed that five of these mutations occurred de novo within two generations; two of them arose in the maternal grandfather and three in the mother. In one of these mothers we could identify a mitotic origin. Mapping of the deletions showed no deletion-prone region within the gene. Furthermore, we could not find any correlation between the particular gene defects and "inhibitor" phenotypes.
Higuchi
M
M
Institut für Klinische Biochemie, Universität Bonn, FRG.
Kochhan
L
L
Schwaab
R
R
Egli
H
H
Brackmann
H H
HH
Horst
J
J
Olek
K
K
D001483:Base Sequence; D002872:Chromosome Deletion; D004252:DNA Mutational Analysis; D015342:DNA Probes; D015246:Deoxyribonuclease EcoRI; D019003:Deoxyribonuclease HpaII; D015252:Deoxyribonucleases, Type II Site-Specific; D005091:Exons; D005169:Factor VIII / Q000235:genetics*; D006467:Hemophilia A / Q000097:blood / Q000235:genetics*; D006801:Humans; D009693:Nucleic Acid Hybridization; D015183:Restriction Mapping
D015342:DNA Probes; D005169:Factor VIII; D015246:Deoxyribonuclease EcoRI; D019003:Deoxyribonuclease HpaII; D015252:Deoxyribonucleases, Type II Site-Specific; C027046:TCGA-specific type II deoxyribonucleases