Spectrum of molecular defects and mutation detection rate in patients with mild and moderate hemophilia A

• Published in: Human mutation Vol. 28; no. 1; pp. 54 - 60
• Main Authors: Bogdanova, Nadja, Markoff, Arseni, Eisert, Roswith, Wermes, Cornelia, Pollmann, Hartmut, Todorova, Albena, Chlystun, Marcin, Nowak-Göttl, Ulrike, Horst, Jürgen
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.01.2007; John Wiley & Sons, Inc
• Subjects: DNA Mutational Analysis - methods; F8 gene; F8 promoter; Factor VIII - chemistry; Factor VIII - genetics; Gene Deletion; Hemophilia A - genetics; Humans; mild hemophilia A; Models, Molecular; molecular modeling; Mutation; Mutation, Missense; Polymorphism, Genetic; Promoter Regions, Genetic - physiology; Protein Structure, Tertiary; RNA Splice Sites - genetics; spectrum of mutations
• ISSN: 1059-7794; 1098-1004; 1098-1004
• DOI: 10.1002/humu.20403

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.