Molecular genetic analysis of severe coagulation factor XI deficiency in six Italian patients

BACKGROUND AND OBJECTIVES: Factor XI (FXI) deficiency is a rare autosomal recessive coagulopathy which is, however, frequent among Ashkenazi Jews. Two mutations, type II (Glu117stop) and type III (Phe283Leu), account for the majority of abnormal alleles in this population. The aim of this study was to analyze the molecular basis of FXI deficiency in six unrelated Italian probands with severe deficiency, a population hitherto largely unexplored. DESIGN AND METHODS: All patients showed unmeasurable functional FXI levels in plasma. Mutational screening was performed by sequencing. Haplotype analysis was performed using intragenic polymorphisms. Expression studies were performed by transient transfection in COS-1 cells. RESULTS: Sequencing identified two novel mutations: a nonsense mutation (Cys118stop) in exon 5 in two probands, and a 6-bp deletion (643-648delATCGAC) in exon 7 in one proband. The Cys118stop is predicted to cause FXI deficiency by a secretion defect and/or by increased mRNA degradation. The 6-bp deletion causes the loss of residues Ile197 and Asp198. There was a remarkable secretion impairment of the deleted FXI protein. In four of the six probands, the type II mutation was found. Haplotype analysis in patients carrying the type II mutation revealed that they share a common haplotype, perhaps derived from a Jewish ancestor. INTERPRETATION AND CONCLUSIONS: The identification and characterization of two novel mutations widen the mutational spectrum of FXI deficiency. Haplotype analysis is compatible with a Jewish origin of the type II mutation. The high occurrence of the type II mutation among Italian patients will be helpful to direct future genetic screenings.