Abstract

Hemophilia A represents a severe most common inherited hemorrhagic disorder caused by heterogeneous mutations, which lead to dysfunctional factor VIII protein. Besides the inversion 22 and intron 1 inversion, the mutations may describe 627 missense and 142 nonsense unique mutations. Changes in the protein sequence induce structural or functional impairment. This study aimed to review mutation in different domains and discuss molecular modeling approach to assess the effects of amino acid substitutions on the topology of FVIII protein domains. A comprehensive literature search was done to analyze the mutations and structural alterations reported in the Hemophilia A gene. Further, our experience in small mutation analyzed with structural alterations was added to the review. Mutation types were used at the hemophilia A mutation, structure, test and resource site (HAMSTeRS). Half of the point mutation in the FVIII gene was found in domain A which includes Glu321Lys, Tyr346Cys, Val357Gly, Thr770Ser, Thr751Ser etc. Exon 14 represents about one half of the coding region and encodes for the FVIII B domain. Several recurrent mutations have been found at 2147, 2150, 2159, 2163 {C1} and 2209, 2300, 2307 (C2) amino-acid positions. Different domains play an important role in the function of FVIII as each contains specific binding active site during the clotting cascade. The review brings forth the functional alterations occurring because of causative mutations in hemophilia A gene.

Key words: Hemophilia a, FVIII gene, mutations, protein modeling.