Fattore VIII ed Emofilia A
Il Fattore VIII è cofattore del Fattore IX per l'attivazione del Fattore X. La manifestazione della carenza di questo cofattore è l'Emofilia A che ha una incidenza di 1 su 10000 individui. Gli individui con Emofilia A sono per la quasi totalità di sesso maschile, poichè il gene del FVIII si trova sul cromosoma sessuale X in singola copia nei maschi.
Haematologica. 2006 Sep;91(9):1261-3.
Contribution of low density lipoprotein receptor-related protein genotypes to coagulation factor VIII levels in thrombotic women.
Marchetti G, Lunghi B, Legnani C, Cini M, Pinotti M, Mascoli F, Bernard F.
Department of Biochemistry and Molecular Biology, University of Ferrara, via Fossato di Mortara n 74, I-44100 Ferrara, Italy.
The contribution of low density lipoprotein (LDL) receptor-related protein (LRP) to variance of factor VIII (FVIII) levels in plasma was investigated in thrombotic women through analysis of frequent LRP genotypes. The G allele of the LRP -25C/G polymorphism, predicting increased LRP expression, was associated with 15% and 18% mean reductions of FVIII activity and protein levels, respectively. The combination of -25C/G LRP polymorphism with FVIII D1241E and ABO polymorphisms produced a gradient of FVIII levels, thus supporting the notion that several factors, acting in FVIII biosynthesis, post-translational modification and removal from circulation, have additive effects on the variance of FVIII levels in plasma.
PMID: 16956829 [PubMed - indexed for MEDLINE]
Thromb Haemost. 2005 Mar;93(3):453-6.
The factor VIII D1241E polymorphism is associated with decreased factor VIII activity and not with activated protein C resistance levels.
Scanavini D, Legnani C, Lunghi B, Mingozzi F, Palareti G, Bernardi F.
Department of Biochemistry and Molecular Biology, Ferrara University, Italy.
Elevated factor VIII (FVIII) levels are a recognized risk factor for venous thrombosis. Recently, family studies suggested that the G allele of the 3951C/G (D1241E) FVIII polymorphism is associated to lower FVIII activity. We investigated in case-control studies both biological effects (FVIII levels and activated protein C sensitivity ratio) and clinical associations (venous thromboembolism) of the D1241E change. Among 145 healthy and 150 thrombotic women, not carriers of known thrombophilic defects, the 1241E allele was associated with 11% reduced (t-test, P<0.05) FVIII levels. The effect on activated protein C sensitivity ratio was not statistically significant. Carriership of the 1241E allele, potentially conferring protection from thrombosis, was found in 22.8% of controls and in 15.3% of cases. In an additional cohort of factor V Leiden carriers (n=283), carriership of the 1241E allele was 25.2% among 143 asymptomatic subjects and 17.1% among 140 thrombotic patients. Our data do not indicate a specific interaction with factor V Leiden. These genotype distributions suggest a mild protective effect from venous thrombosis conferred by 1241E FVIII, masked by other genetic and/or environmental components, and detectable only in very large population studies. Our findings point toward the presence of genetic determinant of coagulation factor levels with a biologically significant role, but with a poor predictive value to estimate thrombotic risk beyond established risk factors.
PMID: 15735794 [PubMed - in process]
Eur J Haematol. 1992 Mar;48(3):152-4.
A novel deletion of FVIII gene associated with variable levels of FVIII inhibitor.
Figueiredo MS, Bernardi F, Zago MA.
Department of Clinical Medicine, School of Medicine, Ribeirao Preto, Brazil.
We describe a novel gross deletion of the factor VIII gene in 5 related patients with severe hemophilia A. The deletion extends from intron 15 to at least 8.5 kb beyond the 3' end of the gene (at least 95 kb of extension), and is associated with variable levels of FVIII inhibitor in 4 of the patients. The carrier detection in the family was based on the abnormal restriction pattern of the partially deleted gene.
PMID: 1559571 [PubMed - indexed for MEDLINE]
Hematol Pathol. 1990;4(4):185-8.
Direct detection of a missense mutation causing severe hemophilia A by PCR amplification and fluorescence scanning.
Marchetti G, Gemmati D, Patracchini P, Volinia S, Castagnoli A, Tosi B, Capelli M, Bernardi F.
Centro di Studi Biochimici delle Patologie del Genoma Umano, Università di Ferrara, Italy.
The amplification of Factor VIII gene-specific sequences, obtained by polymerase chain reaction, was used for hemophilia A carrier detection. Exon 24 sequences were employed in the carrier status determination of a missense mutation causing severe hemophilia A in two unrelated patients. After agarose gel electrophoresis, the digested DNA was subjected to quantitative determination of fluorescence. This technique significantly improves the digest analysis.
PMID: 2074260 [PubMed - indexed for MEDLINE]
Br J Haematol. 1989 Feb;71(2):271-6.
A recurrent missense mutation (Arg----Gln) and a partial deletion in factor VIII gene causing severe haemophilia A.
Bernardi F, Volinia S, Patracchini P, Gemmati D, Boninsegna S, Schwienbacher C, Marchetti G.
Centro di Studi Biochimici sul Morbo di Cooley, Università di Ferrara, Italy.
The presence of gene lesions in coagulation factor VIII (FVIII) gene was investigated in 70 Italian patients severely affected by haemophilia A. cDNA probes specific for exons 14-26 of the FVIII gene were used. In two related patients a gene deletion removes exon 26, a gene lesion similar to that described previously in a British haemophiliac. In exon 24 a C to T transition in the reverse complement strand causes a missense mutation in the coding strand (CGA----CAA, 2209 Arg----Gln). The mutation is located in a very conserved FVIII homology region and severely reduces FVIII activity. By restriction analysis and hybridizations with oligonucleotide probes this gene alteration was found in two unrelated haemophiliacs and in their relatives.
PMID: 2493803 [PubMed - indexed for MEDLINE]
Hum Genet. 1988 Apr;78(4):359-62.
A HindIII RFLP and a gene lesion in the coagulation factor VIII gene.
Bernardi F, Legnani C, Volinia S, Patracchini P, Rodorigo G, DeRosa V, Marchetti G.
Centro di Studi Biochimici sul Morbo di Cooley, Università di Ferrara, Italy.
The presence and inheritance of restriction fragment length polymorphisms (RFLPs) and gene lesions in the coagulation factor VIII gene were investigated in 15 hemophilia families. An abnormal HindIII 2.6-kb band, previously detected in a severe hemophiliac, was observed in a not severely affected patient and also in the normal gene of a woman carrying a hemophilic gene in which the lesions was found. The TaqI site in exon 24 of this defective gene was removed by a C to T transition causing an amino acid change (Arg----Gln). Very low amounts of factor VIII activity and antigen were detected in the severely affected grandson. The presence of the HindIII 2.6-kb fragment in both normal and pathological genes indicates that a factor VIII RFLP without functional meaning was found. Its frequency, determined in 60 chromosomes, is 0.18. Double digestions enabled us to map the polymorphic site 3' to the exon 19.
PMID: 2896159 [PubMed - indexed for MEDLINE]
Hum Genet. 1987 Jul;76(3):253-6.
RFLP analysis in families with sporadic hemophilia A. Estimate of the mutation ratio in male and female gametes.
Bernardi F, Marchetti G, Bertagnolo V, Faggioli L, Volinia S, Patracchini P, Bartolai S, Vannini F, Felloni L, Rossi L, et al.
To investigate the sporadic occurrence of hemophilia A and to estimate the sex ratio of mutation rates directly, 17 families with isolated cases of the disorder were studied by RFLP analysis and by clotting assays. Three RFLPs, one intragenic and two with close linkage to hemophilia A, were used. In eight families the RFLP study excluded the carrier status of the maternal grandmothers. Since hemostatic studies showed that the eight mothers of these propositi were hemophilia carriers, the origin of the newly mutated genes was inferred from the RFLP patterns: six hemophilic genes derived from the normal maternal grandfathers and two, from maternal grandmothers. The data indicate a higher mutation rate in males than in females, as previously suggested by segregation analysis and coagulation studies. However the sex ratio indicated by the RFLP analysis is lower than previously reported and could explain previous conflicting estimates.
PMID: 2885255 [PubMed - indexed for MEDLINE]
