Factor VII (FVII) gene, homologous to the X−linked factor IX gene, has a pivotal role in the initiation of blood coagulation. Severe FVII deficiency is a rare autosomal disorder in which premature death may occur from severe bleeding. The relationship between FVII deficiency and clinical phenotype are poorly defined. We have recently collected information for 483 patients in the frame of a worldwide co−operation(International Registry of FVII deficiency) thus making feasible informative genotype−phenotype studies and comparison with mutations and clinical patterns of the extensively investigated haemophilia B. Since findings in humans and in mouse models indicate that a complete absence of FVII function is not compatible with life, a main goal of the project is to determine the residual FVII function and its relationshipwith FVII gene mutations. An improved evaluation of residual FVII activity toward factor X, in plasma or after in vitro expression of selected mutants, will be achievedthrough fluorogenic substrates. Patients with identical FVII mutations, or grouped for similar coagulation phenotypes, will favour the detection of genetic and biochemical components which modulate the individual risk of bleeding. We plan to characterize intragenic functional polymorphisms, influencing the expression of the altered FVII gene, and frequent polymorphisms in other genes of haemostasis, which could interact with FVII deficiency. Global assays of coagulation, anticoagulation and fibrinolysis function, and factor specific assays, will be performed in plasma. Reconstituted systems will be also exploited as in vitro models to dissect the interaction of modifiers with FVII deficiency. Studies of FVII variants with increased intrinsic activity or stability, potentially therapeutic tools, will be conducted in plasma. These studies will improve the understanding of the molecular bases of FVII deficiency and will favour its treatment on an individual basis.
Progetto TELETHON: Non−conventional therapeutic strategies for inherited disorders of hemostasis.
BERNARDI, Francesco
2005
Abstract
Factor VII (FVII) gene, homologous to the X−linked factor IX gene, has a pivotal role in the initiation of blood coagulation. Severe FVII deficiency is a rare autosomal disorder in which premature death may occur from severe bleeding. The relationship between FVII deficiency and clinical phenotype are poorly defined. We have recently collected information for 483 patients in the frame of a worldwide co−operation(International Registry of FVII deficiency) thus making feasible informative genotype−phenotype studies and comparison with mutations and clinical patterns of the extensively investigated haemophilia B. Since findings in humans and in mouse models indicate that a complete absence of FVII function is not compatible with life, a main goal of the project is to determine the residual FVII function and its relationshipwith FVII gene mutations. An improved evaluation of residual FVII activity toward factor X, in plasma or after in vitro expression of selected mutants, will be achievedthrough fluorogenic substrates. Patients with identical FVII mutations, or grouped for similar coagulation phenotypes, will favour the detection of genetic and biochemical components which modulate the individual risk of bleeding. We plan to characterize intragenic functional polymorphisms, influencing the expression of the altered FVII gene, and frequent polymorphisms in other genes of haemostasis, which could interact with FVII deficiency. Global assays of coagulation, anticoagulation and fibrinolysis function, and factor specific assays, will be performed in plasma. Reconstituted systems will be also exploited as in vitro models to dissect the interaction of modifiers with FVII deficiency. Studies of FVII variants with increased intrinsic activity or stability, potentially therapeutic tools, will be conducted in plasma. These studies will improve the understanding of the molecular bases of FVII deficiency and will favour its treatment on an individual basis.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
