A novel factor XI missense mutation (Val371Ile) in the activation loop is responsible for a case of mild type II factor XI deficiency

Cristina Bozzao, Valeria Rimoldi, Rosanna Asselta, Meytal Landau, Rossella Ghiotto, Maria L. Tenchini, Raimondo De Cristofaro, Giancarlo Castaman, Stefano Duga

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)6128-6138
Number of pages11
JournalFEBS Journal
Volume274
Issue number23
DOIs
Publication statusPublished - Dec 2007

Keywords

  • Coagulation factor XI deficiency
  • Functional characterization
  • Missense mutation
  • Mutational screening
  • Type II defect

ASJC Scopus subject areas

  • Biochemistry

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