A novel factor XI missense mutation (Val371Ile) in the activation loop is responsible for a case of mild type II factor XI deficiency.
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.
Bozzao
Cristina
C
Department of Biology and Genetics for Medical Sciences, University of Milan, Italy.
Rimoldi
Valeria
V
Asselta
Rosanna
R
Landau
Meytal
M
Ghiotto
Rossella
R
Tenchini
Maria L
ML
De Cristofaro
Raimondo
R
Castaman
Giancarlo
G
Duga
Stefano
S
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
D017077:Culture Media, Conditioned; D011994:Recombinant Proteins; D007532:Isoleucine; D005172:Factor XI; D013917:Thrombin