Molecular and Clinical Characterization of 7 Iranian Patients with Severe Congenital Factor V Deficiency: Identification of 4 Novel Mutations

Background and Aims: Congenital factor V (FV) deficiency is a rare bleeding disorder with 1 in 1000000 persons in the general population. Individuals with FV activity <1% and very low FV antigen levels are characterized as severe FV deficient patients. Little data is available about the molecular basis of this bleeding disorder in Iran. Materials and Methods: We analyzed 7 unrelated Iranian FV deficient patients regarding clinical manifestation and genotype. The molecular dynamic simulation was carried out to analyze the effect of novel mutations on the FV structure. Results: All cases had recurrence epistaxis, oral cavity bleeding, and hematoma were frequent in our patients. The molecular analysis led to the identification of three already reported mutations (IVS 19+3 A>T, 4014-4017 del TCAG and p.P419R) and four novel mutations (IVS9-1 G>C, Y478D, L1844P, I1556T) in the FV gene of our patients. According to the molecular modeling results, it seems that in the two mutations Y478D and I1556T, an increased number of H-bonds in mutant proteins compared to natural ones reduces the flexibility and increases the stability of the mutant proteins. The results also show that in L1844P and I1556T mutations, the total solvent accessible surface area (both hydrophilic and hydrophobic) significantly decreases compared to the natural variants. Conclusion: Identifying the causative mutation in patients with FV deficiency helps to determine the molecular basis of this bleeding disorder and gain more insight into explaining the variable clinical manifestations of patients with FV deficiency.