title: Gene mutations and three-dimensional structural analysis in 13 families with severe factor X deficiency.
abstract: 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-->T and IVS2-3, T-->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.
authors.affiliation: Angelo Bianchi Bonomi Haemophilia and Thrombosis Centre, Luigi Villa Foundation, IRCCS Maggiore Hospital and University of Milan, Via Pace, 9-20122 Milan, Italy. flora.peyvandi@unimi.it
authors.forename: Flora
authors.initials: F
authors.lastname: Peyvandi
authors.forename: Marzia
authors.initials: M
authors.lastname: Menegatti
authors.forename: Elena
authors.initials: E
authors.lastname: Santagostino
authors.forename: Sepideh
authors.initials: S
authors.lastname: Akhavan
authors.forename: James
authors.initials: J
authors.lastname: Uprichard
authors.forename: David J
authors.initials: DJ
authors.lastname: Perry
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Perkins
authors.forename: Pier M
authors.initials: PM
authors.lastname: Mannucci
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D005170:Factor X / Q000235:genetics*; D005171:Factor X Deficiency / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D010641:Phenotype; D011487:Protein Conformation; D017510:Protein Folding
chemical_list: D005170:Factor X