Gene mutations and three‐dimensional structural analysis in 13 families with severe factor X deficiency

Abstract

Summary. Factor X (FX) deficiency is a rare autosomal recessive disorder. The phenotype and genotype of 15 Iranian patients with FX deficiency from 13 unrelated families with a high frequency of consanguinity were analysed. Five different assays identified four patients from three families with a discrepancy between low-FX coagulant activity (FX:C) and higher-FX antigen (FX:Ag) (a type II deficiency). The remaining 11 patients had parallel reductions of FX:C and FX:Ag (a type I deficiency). Nine different homozygous candidate mutations were identified, of which eight were novel. The four type II cases were associated with an Arg()1)Thr missense mutation in the prepropeptide: Arg()1) is highly conserved in all vitamin K-dependent proteins. Four type I mutations (Gly78Asp, Cys81Tyr, Gly94Arg and Asp95Glu) were localized to the EGF-1 and EGF-2 domains, for which molecular views showed that the protein folding would be disrupted. The type I mutation Gly222Asp was localized in the catalytic domain of FX, and is sufficiently close to the Asp-His-Ser catalytic triad to disrupt its correct protein folding. The two type I splice site mutations were IVS1+3, A fi T and IVS2-3, T fi G. These novel homozygous FX mutations were consistent with their phenotypes and agree with experimental data from knockout mice, indicating that FX is an essential protein for survival.

CoagMDB: a database analysis of missense mutations within four conserved domains in five vitamin K-dependent coagulation serine proteases using a text-mining tool

“…3d). This region forms a loop composed of a b-strand K followed by an a-helix A3 [Peyvandi et al, 2002] that is close to the surface but not in close proximity to the active site (Fig. 3d).…”

“…The EGF structure is most often seen as one a-helix A1 and up to four b-strands B1 to B4 [Akhavan et al, 2000;Peyvandi et al, 2000Peyvandi et al, , 2002 linked by three disulfide bridges (Fig. 3b and c).…”

“…The 15 b-strands in the SP domain are assigned letters A to O, and there are up to four a-helices A1 to A4 [Akhavan et al, 2000;Peyvandi et al, 2000Peyvandi et al, , 2002. The chymotrypsin residue numbering is denoted by a c prefix.…”

“…Until now, mutations within the coagulation serine proteases have only been analyzed in terms of single proteases and their secondary structures and residue accessibilities [Akhavan et al, 2000;Peyvandi et al, 2000Peyvandi et al, , 2002Saunders et al, 2005]. No mutational analysis has been presented in the context of what is known about other serine protease mutations.…”

Factor X Deficiency with Heterozygous Mutations of Novel p.G435S and Known p.G244R in a Patient Presenting with Severe Umbilical Hemorrhage

“…Previous studies conducted in Japan reported that most patients were aged 10 years or older and presented with subcutaneous hemorrhage, epistaxis, menorrhagia, gastrointestinal bleeding, and bleeding after surgery or trauma. However, the severity of FX deficiency varies from mild to serious, and depends on the degree of residual plasma FX activity [8][9][10].…”