title: Characterization of seven novel mutations causing factor XI deficiency.
abstract: OBJECTIVE
  Factor XI (FXI) deficiency is a rare autosomal recessive disorder, the main manifestation of which is injury-related bleeding. The disorder is rare in most populations, but common among Jews in whom two mutations, E117X and F283L, account for 98% of cases. Other mutations, C38R and C128X, are prevalent in French Basques and Britons, respectively. Additional sporadic mutations have been described in most parts of the world. The objective of this study was to identify the mutations in 15 unrelated FXI-deficient patients and characterize missense mutations by expression in baby hamster kidney (BHK) cells.
  
  
  METHODS
  Clinical and laboratory information and DNA samples were obtained from the patients and mutations were identified by sequencing. Missense mutations were expressed in BHK cells and their effect on FXI secretion and dimerization was assessed using enzyme-linked immunosorbent assay and immunoblotting.
  
  
  RESULTS
  Of 16 mutations detected, seven are novel including two deletions, one splice site and four missense mutations. Expression of the four novel missense mutations (C58Y, Y427C, C527Y and V20A) in cells revealed no secretion of FXI-C58Y, Y427C and C527Y and secretion of only 22% of normal in the medium for FXI-V20A. Secretion of FXI from BHK cells harboring a previously reported E297K substitution cells was also impaired (4.5% of wild-type). Homodimerization was normal for all five mutants.
  
  
  CONCLUSIONS
  Defective homodimerization of FXI was previously recognized as a major mechanism for defective secretion of FXI from producing cells. In this study, five FXI missense mutations (four novel) were associated with impaired secretion albeit normal dimerization, underscoring the existence of other mechanisms for defective secretion.
authors.affiliation: The Amalia Biron Research Institute of Thrombosis and Hemostasis, Chaim Sheba Medical Center, Tel-Hashomer and Sackler Faculty of Medicine, Tel Aviv University, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Zucker
authors.forename: Ariella
authors.initials: A
authors.lastname: Zivelin
authors.forename: Meytal
authors.initials: M
authors.lastname: Landau
authors.forename: Ophira
authors.initials: O
authors.lastname: Salomon
authors.forename: Gili
authors.initials: G
authors.lastname: Kenet
authors.forename: Frederic
authors.initials: F
authors.lastname: Bauduer
authors.forename: Michel
authors.initials: M
authors.lastname: Samama
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Conard
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Denninger
authors.forename: Abu-Samra
authors.initials: AS
authors.lastname: Hani
authors.forename: Micheline
authors.initials: M
authors.lastname: Berruyer
authors.forename: Donald
authors.initials: D
authors.lastname: Feinstein
authors.forename: Uri
authors.initials: U
authors.lastname: Seligsohn
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D006224:Cricetinae; D019281:Dimerization; D005172:Factor XI / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D005173:Factor XI Deficiency / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics; D020836:Protein Structure, Quaternary
chemical_list: D005172:Factor XI