Structural Investigation of Two Novel Mutations in Coagulation Factor V by Molecular Modeling

摘要

Human coagulation factor V (FV) provides an essential function in the coagulation pathway. As a non-enzymatic cofactor of the prothrombinase complex, it is required for the rapid generation of thrombin [1, 2]. The gene for coagulation FV is located on chromosome Iq24.2 and spans more then 80 kilobases (kb) [3]. It consists of 25 exons encoding a 25 amino acids leader peptide and 2196 amino acids mature protein organized in A1-A2-B-A3-C1-C2 domain structure [4]. The activated factor Va is composed of a heavy chain (domains Al and A2, Alal-Arg709) and a light chain (domains A3, Cl, and C2, Serl546-Tyr2196), noncovalently associated in the presence of divalent metal ions.Deficiency of coagulation factor V or parahemophilia represents a rare, auto-somal recessive bleeding disorder with an incidence about approximately one in one million. The phenotypic expression of the disease varies largely from an asymptomatic heterozygotes to mild/moderate or severe bleedings in homozygotes [5]. The genetic basis of FV deficiency is still not well explored. The mutational spectrum is characterized by a remarkable genetic heterogeneity and an uneven distribution of mutations throughout the FV gene. Here we describe two novel mutations associated with factor V deficiency and present the computer assisted modeling of these mutations.