Mutational analysis of ectopic factor VIII transcripts from hemophilia A patients: identification of cryptic splice site, exon skipping and novel point mutations

Tavassoli, Kamiab; Eigel, Antonin; Pollmann, H.; Horst, Jürgen

doi:10.1007/s004390050543

Cited by 23 publications

(30 citation statements)

References 16 publications

(13 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Patients with severe molecular defects, such as a large deletion, a nonsense mutation, and intron 22 inversions, show a higher frequency of developing inhibitors than patients with milder mutations [33]. The deletion mutation of two nucleotides (GT) at the 5 0 -donor splicing site found in our patient may result in a loss of accurate mRNA processing, subsequently being associated with the severity of hemophilia [34,35].…”

Section: Discussionmentioning

confidence: 75%

Mutation analysis of factor VIII in Korean patients with severe hemophilia A

et al. 2010

View full text Add to dashboard Cite

Hemophilia A is an X-linked recessive disorder caused by mutations of the factor VIII gene. The mutation spectrum has been reported in various populations, but not in Koreans. Mutation analysis of the factor VIII gene was performed in 22 unrelated Korean patients with severe hemophilia A. We extracted genomic DNA from their blood, and assessed intron inversions, deletions, and point mutations by direct DNA sequencing. A multiplex ligation-dependent probe amplification gene dosage assay was also performed to identify exon deletions. Disease-causing mutations were identified in all patients, of which four cases were previously unreported. Seven intron 22 inversions, nine point mutations (6 nonsense mutations and 3 missense mutations), and four small rearrangements were identified. One multi-exon deletion and one 5'-donor splicing site mutation were also observed. Four novel mutations (one small deletion, one multiple exon deletion, one missense, and one splice site mutation) were detected, and point mutations were predominant (40.9%), followed by intron 22 inversions (31.8%). Further studies are required in order to establish a solid conclusion regarding the prevalence of various mutations in the Korean population.

show abstract

Section: Discussionmentioning

confidence: 75%

Mutation analysis of factor VIII in Korean patients with severe hemophilia A

et al. 2010

View full text Add to dashboard Cite

show abstract

“…D116G, S207I, and K425R were previously described in severely affected patients [Becker et al, 1996;Higuchi et al, 1991], and E1875G was detected in a moderately affected patient [Tavassoli et al, 1997].…”

Section: Missense Mutationsmentioning

confidence: 74%

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

Bogdanova

Markoff²,

Pollmann³

et al. 2005

Hum. Mutat.

Self Cite

View full text Add to dashboard Cite

Hemophilia A is the most frequently occurring X-linked bleeding disorder, affecting one to two out of 10,000 males worldwide. Various types of mutations in the F8 gene are causative for this condition. It is well known that the most common mutation in severely affected patients is the intron 22 inversion, which accounts for about 45% of cases with F8 residual activity of less than 1%. Therefore, the aim of the present study was to determine the spectrum and distribution of mutations in the F8 gene in a large group of patients with severe hemophilia A who previously tested negative for the common intron 22 inversion. Here we report on a mutation analysis of 86 patients collected under the above-mentioned criterion. The pathogenic molecular defect was identified in all patients, and thus our detection rate was virtually 100%. Thirty-four of the identified mutations are described for the first time. The newly detected amino acid substitutions were scored for potential gross or local conformational changes and influence on molecular stability for every single F8 domain with available structures, using homology modeling.

show abstract

“…Apart from three examples of direct AG creation in exons (28–30), three de novo sites were produced by point mutations in position –3 (31–33), one in position –5 (34) and three in position –6 (35–37) relative to the new intron–exon junction. Three aberrant exonic 3′ss resulted from mutations of the predicted BP adenosine (38,39) or conserved uridine in position –2 relative to BP (40), known hot-spots of single-nucleotide substitutions in the human BPS (15). Several aberrant 3′ss in exons resulted from more distant mutations (39,41), highlighting the importance of PPT, BPS and distant auxiliary splicing signals for the activation of 3′ss in this category.…”

Section: Resultsmentioning

confidence: 99%

Biased exon/intron distribution of cryptic and de novo 3' splice sites

Královičová

Christensen

Vořechovský

2005

Nucleic Acids Research

View full text Add to dashboard Cite

We compiled sequences of previously published aberrant 3′ splice sites (3′ss) that were generated by mutations in human disease genes. Cryptic 3′ss, defined here as those resulting from a mutation of the 3′YAG consensus, were more frequent in exons than in introns. They clustered in ∼20 nt region adjacent to authentic 3′ss, suggesting that their under-representation in introns is due to a depletion of AG dinucleotides in the polypyrimidine tract (PPT). In contrast, most aberrant 3′ss that were induced by mutations outside the 3′YAG consensus (designated ‘de novo’) were in introns. The activation of intronic de novo 3′ss was largely due to AG-creating mutations in the PPT. In contrast, exonic de novo 3′ss were more often induced by mutations improving the PPT, branchpoint sequence (BPS) or distant auxiliary signals, rather than by direct AG creation. The Shapiro–Senapathy matrix scores had a good prognostic value for cryptic, but not de novo 3′ss. Finally, AG-creating mutations in the PPT that produced aberrant 3′ss upstream of the predicted BPS in vivo shared a similar ‘BPS-new AG’ distance. Reduction of this distance and/or the strength of the new AG PPT in splicing reporter pre-mRNAs improved utilization of authentic 3′ss, suggesting that AG-creating mutations that are located closer to the BPS and are preceded by weaker PPT may result in less severe splicing defects.

show abstract

Mutational analysis of ectopic factor VIII transcripts from hemophilia A patients: identification of cryptic splice site, exon skipping and novel point mutations

Cited by 23 publications

References 16 publications

Mutation analysis of factor VIII in Korean patients with severe hemophilia A

Mutation analysis of factor VIII in Korean patients with severe hemophilia A

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

Biased exon/intron distribution of cryptic and de novo 3' splice sites

Contact Info

Product

Resources

About