Eight novel mutations in FXI gene

Background. Factor XI deficiency is a an autosomally inherited bleeding disorder characterized by an extreme heterogeneity as to bleeding tendency, often independent from circulating FXI levels. About 50 mutations in FXI gene has been published so far (O’Connell, 2005). Aim of the study. We report 8 novel mutations in FXI gene in 6 patients with severe and 3 with partial FXI deficiency. Methods. The whole coding sequence and intron-exon boundaries of FXI gene were PCR-amplified and directly sequenced on ABIPrism. Six patients with severe FXI deficiency (FXI:C < 1 % to 5 %; FXI:Ag 3 to 5 %) and 3 with partial FXI deficiency (FXI:C 20 to 36 %; FXI:Ag 32 to 45 %) were characterized. None of them was of Jewish ancestry. Results. Two patients were homozygous for two novel mutations (Cys122Tyr and IVS2+5 insGA, IVS2+6 T>G) and four were compound heterozygotes (novel mutations underlined) (Arg54X/Gly336Arg; Cys122Tyr/18071delGA; Phe283Leu/Ala412Thr; Arg54Pro/?). In the heterozygotes, three novel mutations were detected (14001delAAACTGAGAGT in intron 8; 5508delGGA in exon 3; Cys38Trp in exon 3). The Cys122Tyr mutation disrupts Cys122-Cys128 disulfide pairing in Apple 2 domain responsible for substrate binding site in FXIa. The Cys38Trp mutations disrupts Cys38-Cys32 disulfide pairing in Apple 1 domain, responsible for ligand binding site in FXI. Conclusions. This report confirms the wide heterogeneity of molecular basis of FXI deficiency in patients not belonging to Jewish community.