Identification of four novel mutations in the factor VIII gene: Three missense mutations (E1875G, G2088S, I2185T) and a 2-bp deletion (1780delTC)

Tavassoli, Kamiab; Eigel, Antonin; Dworniczak, Bernd; Valtseva, Elena; Horst, Jürgen

doi:10.1002/humu.1380110183

Cited by 6 publications

(3 citation statements)

References 16 publications

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“…Cleavage by thrombin or FXa after R372 is important for generation of FVIIIa [25]; consistent with this, subject M829 has moderately severe HA. The substitution G2088S was previously reported in one German family, where it was also associated with moderately severe HA [26], similar to the Moldovan subject M840.…”

Section: Missense Mutationssupporting

confidence: 70%

Factor VIII mutations in 42 Moldovan haemophilia A families, including 12 that are novel

Sirocova¹,

Tsourea²,

Vicol³

et al. 2009

Haemophilia

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Haemophilia A (HA) is a bleeding disorder caused by mutations within the X-linked F8 gene. A series of 42 unrelated Moldovan patients with HA had their disease-causative mutation determined to provide clinically valuable genotyping information for a historically underserved population and to utilize factor VIII (FVIII) structural information to analyse the effects of haemophilic missense substitutions. DNA samples were analysed to detect intron 22 and intron 1 inversions followed by heteroduplex analysis of PCR-amplified fragments containing all exonic sequences. Missense sites identified by DNA sequencing were visualized in the recently described crystal structures of human FVIII. Of the 26 different point mutations, 12 were novel. Gel electrophoresis identified samples with a second major DNA band that migrated abnormally; these amplified products were sequenced. Thirteen intron 22 inversions and one intron 1 inversion were found. Two patients had large, partial gene deletions and there were six frameshift, two non-sense, two splicing and 16 missense genotypes. Two subjects with an intron 22 inversion and one with a large, partial gene deletion developed an alloimmune inhibitor. Their localization suggests intra- and possibly inter-molecular interactions that are important for the structural integrity and/or procoagulant function of FVIII.

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Section: Missense Mutationssupporting

confidence: 70%

Factor VIII mutations in 42 Moldovan haemophilia A families, including 12 that are novel

Sirocova¹,

Tsourea²,

Vicol³

et al. 2009

Haemophilia

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“…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).…”

Section: Resultsmentioning

confidence: 99%

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

Královičová

Christensen

Vořechovský

2005

Nucleic Acids Research

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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.

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“…Up to now we systematically analyzed factor VIII gene for pathological defects in 50 cases of severe hemophilia A, referred to our institute for molecular diagnosis [Tavassoli et al, 1997;Tavassoli et al, 1998a;Tavassoli et al, 1998b;Tavassoli et al, 1999;Möller-Morlang et al, 1999;unpublished data]. Large deletions and the common intron 22-inversion, a frequent cause for severity of the disease, were previously excluded in these patients using Southern-blot analyses.…”

Section: Introductionmentioning

confidence: 99%

Prevalence of small rearrangements in the factor VIII gene F8C among patients with severe hemophilia A

Bogdanova

Markoff²,

Pollmann

et al. 2002

Hum. Mutat.

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Hemophilia A is a common X-linked bleeding disorder caused by various types of mutations in the factor VIII gene F8C. The most common intron 22-inversion is responsible for about 40% of the severe hemophilia A cases while large deletions, point mutations and small (less than 100 bp) deletions or insertions are responsible for the disease in the rest of patients. We report on nine novel (6 deletions, two indels and one partial duplication) and five recurrent small rearrangements identified in 15 German patients with severe hemophilia A, negative for the intron 22-inversion. c.2208-2214delTTATTAC/c.2207-2215insCTCTT and c.4665-4678del/c.4664-4678insAAGGAA identified in the present study are the first small indels described in the factor VIII gene. Our analyses suggest that the prevalence of this type of mutations (predominantly located in exon 14) among patients with severe phenotype and negative for the common intron 22-inversion, is about 30%. The correlation between these molecular defects and formation of factor VIII inhibitors as well as the parental origin of the de novo mutations are evaluated. Finally we show that denaturing HPLC (DHPLC) and classic heteroduplex analysis (HA) are able to detect these sequence alterations on 100% and could be preferred as a screening approach when analysing for mutations in factor VIII in severely affected patients.

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Identification of four novel mutations in the factor VIII gene: Three missense mutations (E1875G, G2088S, I2185T) and a 2-bp deletion (1780delTC)

Cited by 6 publications

References 16 publications

Factor VIII mutations in 42 Moldovan haemophilia A families, including 12 that are novel

Factor VIII mutations in 42 Moldovan haemophilia A families, including 12 that are novel

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

Prevalence of small rearrangements in the factor VIII gene F8C among patients with severe hemophilia A

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