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

Sedighe Satari, Mahmood Shams, S. Tabibian, F. Zaker, M. Rezvany
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Abstract

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.
7例伊朗严重先天性因子V缺乏患者的分子和临床特征:4个新突变的鉴定
背景和目的:先天性因子V (FV)缺乏症是一种罕见的出血性疾病,在普通人群中发病率为百万分之一。我们患者的FV基因具有FV活性T, 4014-4017 del TCAG和p.P419R)和四个新突变(ivs9 - 1g >C, Y478D, L1844P, I1556T)的个体。从分子建模结果来看,在Y478D和I1556T两个突变中,突变蛋白中氢键数量的增加似乎降低了突变蛋白的灵活性,增加了突变蛋白的稳定性。结果还表明,在L1844P和I1556T突变中,总溶剂可及表面积(亲水性和疏水性)比自然变异显著减少。结论:确定FV缺乏症患者的致病突变有助于确定这种出血性疾病的分子基础,并有助于更好地解释FV缺乏症患者多变的临床表现。
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