title: A novel factor XI missense mutation (Val371Ile) in the activation loop is responsible for a case of mild type II factor XI deficiency.
abstract: Coagulation factor XI (FXI) is the zymogen of a serine protease that, when converted to its active form, contributes to blood coagulation through proteolytic activation of factor IX. FXI deficiency is typically an autosomal recessive disorder, characterized by bleeding symptoms mainly associated with injury or surgery. Of the more than 100 FXI gene mutations reported in FXI-deficient patients, most are associated with a proportional decrease in FXI functional and immunologic levels (type I defects), whereas only a few mutations leading to the presence of dysfunctional molecules in plasma have been molecularly analyzed to date (type II deficiencies). We report the functional and molecular characterization of a missense mutation (Val371Ile) identified, in the heterozygous state, in a 25-year-old Italian male with mild FXI deficiency. Laboratory analysis revealed reduced functional FXI levels (34%), but normal antigen levels (102%), distinctive of a type II defect. Given the proximity of Val371 to the FXI activation site, a possible interference with zymogen activation was postulated. Expression experiments of the FXI-Val371Ile recombinant protein, followed by activation assays, showed both a different time course in FXI activation and a slight delay in factor IX activation by thrombin-activated FXI.
authors.affiliation: Department of Biology and Genetics for Medical Sciences, University of Milan, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Bozzao
authors.forename: Valeria
authors.initials: V
authors.lastname: Rimoldi
authors.forename: Rosanna
authors.initials: R
authors.lastname: Asselta
authors.forename: Meytal
authors.initials: M
authors.lastname: Landau
authors.forename: Rossella
authors.initials: R
authors.lastname: Ghiotto
authors.forename: Maria L
authors.initials: ML
authors.lastname: Tenchini
authors.forename: Raimondo
authors.initials: R
authors.lastname: De Cristofaro
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Castaman
authors.forename: Stefano
authors.initials: S
authors.lastname: Duga
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution; D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D020134:Catalytic Domain; D002522:Chlorocebus aethiops; D017077:Culture Media, Conditioned / Q000032:analysis; D005172:Factor XI / Q000235:genetics*; D005173:Factor XI Deficiency / Q000235:genetics* / Q000378:metabolism; D005808:Genes, Recessive; D006579:Heterozygote; D006801:Humans; D007532:Isoleucine / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D008958:Models, Molecular; D020125:Mutation, Missense; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000378:metabolism; D013917:Thrombin / Q000494:pharmacology
chemical_list: D017077:Culture Media, Conditioned; D011994:Recombinant Proteins; D007532:Isoleucine; D005172:Factor XI; D013917:Thrombin