Compound Heterozygosity for a Novel Mutation Combined with G Insertion in Exon 13 Causes Severe Factor XI Deficiency in Patients of Japanese Origin.

Factor XI (FXI) deficiency is a rare autosomal recessive coagulopathy. However, it is one of the most common inherited disorders among Ashkenazi Jews. FXI deficiency is characterized by undetectable levels of FXI antigen and coagulant activity. Patients with FXI deficiency usually suffered from mild to moderate bleeding manifestations. Up to now, more than 80 gene mutations responsible for FXI deficiency have been reported including three common mutations (Type I, II and III) in Ashkenazi Jews. However, it has been reported that significantly higher frequency of allelic heterogeneity has been observed in different ethnic groups. We have studied the molecular basis of this disease in a Japanese family. Two children with FXI deficiency who are siblings have frequent epistaxis. Blood coagulation tests showed severely prolonged aPTT with normal PT. FXI coagulant activities of both patients were less than 1% activity. Their father and mother had normal aPTT, but the activities of FXI in parents showed 45% and 52% activities, respectively. Prolonged aPTT restored to normal range by the addition of recombinant Factor VIIa (NovoSeven^R) dose-dependently, indicating the possible efficacy for the replacement therapy in this disorder. FXI gene mutations were screened by a PCR. We identified a novel mutation, C to G transversion in exon 12 in the FXI gene. The C to G transversion in exon 12 results in a missense mutaion (Q433E). That leads to the disruption of catalytic domain structure of FXI molecule. Another mutation was found in G insertion in exon 13, which was previously reported in only one Japanese patient, causes the frameshift, resulting in substitution of last 105 amino acids (Tyr503-Val607) with 32 abnormal amino acid residues. This change also induces the destruction of the catalytic domain of FXI. Thus, the compound heterozygous novel mutations found in Japanese are not identical to those in Ashkenazi Jews, suggesting that this mutation may not be of the same ancestry.