Molecular genetics and biology of congenital hemorrhagic diseases

Coagulation deficiences causing bleeding are X-linked or autosomally inherited, the latter being the most rare, with an estimated prevalence in the general population from about 1:500,000 (FVII deficiency) to 1:2,000,000 (prothrombin deficiency). Increased frequency of homozygotes is observed in those countries where consanguineous marriages are relatively common. Gene size and specific mutational mechanisms, as C to T transition in CpG sites and illegitimate recombination, shape the frequency of mutations and deficiencies. The molecular genetic defects have been extensively investigated and characterized for frequent and rare coagulation deficiencies. Analysis of gene mutations highlights their extreme heterogeneity with a majority of causative missense changes. The expression of selected mutants is useful to test residual antigen, function or mRNA of coagulation factors, and to evaluate the contribution of mutation to the clinical phenotype. The comparison of FVII deficiency with haemophilia B provides a valuable model for evaluation of mutation spectra in autosomal or X-linked homologous genes. FVII and FX deficiencies show extensive similarity in their mutational patterns, with potentially null mutations less represented in FVII than FIX gene. A few coagulation factors circulate as multisubunit proteins (FXIII, fibrinogen, FXI and von Willebrand factor). This implies that heterozygous mutations can cause severe quantitative deficiencies (dominant negative effect) through formation of mutant and wild-type polypeptide heterodimers. This mechanism has been suggested for von Willebrand disease and also for factor XI deficiency. Several studies indicate the presence of genetic and acquired factors modulating the clinical expression of deficiencies. Genetic factors have been found to have a major effect on plasma concentrations of haemostatic proteins. In particular for FVII, they account for 57-63% of level variations. Intragenic polymorphisms strongly contribute to FVII levels in normal subjects and up to 5-fold differences in FVIIa values are associated to different genotypes. Combination of polymorphisms and gene mutations could contribute to clinical variability. Several studies have highlighted the biosynthetic pathways of coagulation factors, which include several post-translational modifications required for factor secretion and function. Alterations in genes, which participate in the protein maturation process, are candidate to produce or modulate coagulation deficiencies, and might contribute to explain their large variability in the clinical expression. A good example is offered by combined deficiency of coagulation factors V and VIII, in which most of the patients have mutations in genes involved in the intracellular transport of both factors. Other candidates are suggested by combined deficiency of all vitamin K-dependent coagulation factors, a rare bleeding disorder caused by mutations in the genes coding for the g-glutamyl carboxylase and for the enzymes involved in the recycling of the reduced form of vitamin K. Further complexity in the understanding of genotype-phenotype relationships is represented by the delicate balance between coagulation/anticoagulation that ultimately produces the haemostatic phenotype. Key coagulation factors, like thrombin and FV, have procoagulant as well as anticoagulant functions. Coinheritance of FV Leiden leads to enhanced thrombin generation and can mitigate clinical course in patients with severe FVII deficiency due to homozygosity for a splicing mutation, indicating that abnormalities could counterbalance each other. The knowledge of mechanisms underlying the phenotypic diversity of the coagulation deficiencies could improve genetic counselling and provide elements for individually oriented prophylaxis/therapy approaches.