Nadja Bogdanova and Arseni Markoff contributed equally to this work.
Spectrum of molecular defects and mutation detection rate in patients with mild and moderate hemophilia A†
Article first published online: 13 SEP 2006
© 2006 Wiley-Liss, Inc.
Volume 28, Issue 1, pages 54–60, January 2007
How to Cite
Bogdanova, N., Markoff, A., Eisert, R., Wermes, C., Pollmann, H., Todorova, A., Chlystun, M., Nowak-Göttl, U. and Horst, J. (2007), Spectrum of molecular defects and mutation detection rate in patients with mild and moderate hemophilia A. Hum. Mutat., 28: 54–60. doi: 10.1002/humu.20403
Communicated by Arupa Ganguly
- Issue published online: 7 DEC 2006
- Article first published online: 13 SEP 2006
- Manuscript Accepted: 29 JUN 2006
- Manuscript Received: 3 APR 2006
- Bayer Vital GmbH; ZLB Behring AG
- F8 gene;
- mild hemophilia A;
- spectrum of mutations;
- molecular modeling;
- F8 promoter
The amount of residual F8 (FVIII:C) determines the clinical severity of hemophilia A. Recently, we showed that the mutation detection rate in severely affected male patients (FVIII:C<1% of normal) is virtually 100% when testing for the common intron 22–/intron 1– inversions and big deletions, followed by genomic sequencing of the F8 gene. Here we report on the spectrum of mutations and their distribution throughout the F8 gene sequence in 135 patients with moderate (n=23) or mild (n=112) hemophilia A. In contrast to the severe form of the disorder, analysis on the genomic level failed to detect the molecular defect in ∼4% of the moderately and in ∼12% of the mildly affected patients. A total of 36 of the mutations identified in this study are novel. The vast majority of the detected changes were missense. The newly detected amino acid substitutions were scored for potential distant or local conformational changes and influence on molecular stability for every single F8 domain with available structures, using homology modeling. Two molecular changes in the promoter region of the factor VIII gene (c.–112G>A and –219C>T), affecting the core segment (minimal promoter) were detected in two patients with mild hemophilia A. To our knowledge this is the first report on promoter mutations in the F8 gene. Hum Mutat 28(1), 54–60, 2007. © 2006 Wiley-Liss, Inc.