Type II mutation (Glu117stop) causes factor XI deficiency by inducing allele specific mRNA degradation

Severe factor XI (FXI) deficiency is a bleeding disorder generally inherited as an autosomal recessive trait and characterized by haemorrhagic symptoms mainly associated with injury or surgery. The disease has been described in most populations but is particularly common in Jews, where a heterozygous frequency of 9% has been reported. Among known genetic defects in the FXI gene, the type II mutation (Glu117stop) is highly frequent in Ashkenazi and Iraqi Jews, and was repeatedly found also in other populations, always associated with the same founder haplotype. This nonsense mutation, which creates a premature termination codon (PTC) in exon 5, is predicted to cause the synthesis of a truncated protein, which is absent from patients’ plasma. However, transcripts harboring PTCs are also known to frequently undergo an allele specific degradation through the nonsense-mediated mRNA decay mechanism, which prevents cells from the deleterious effects (i.e. dominant negative or gain-of-function) of truncated protein possibly originating from stable nonsense transcripts. So far, no evidence has been reported on the effect of the Glu117stop mutation on FXI mRNA metabolism. In this study, platelet-derived mRNAs from three Italian patients carrying the type II mutation in the heterozygous state were analyzed by RT-PCR and sequencing, and compared to their corresponding genomic sequence. In all patients, only transcripts originating from the wild-type allele were detected, suggesting the selective degradation of FXI mRNAs harboring the PTC. Moreover, no evidence of alternative splicing of FXI exon 5, previously reported to occur in platelets, was found in these patients. It will be interesting to extend analysis to other FXI null mutations in order to evaluate the effect of premature termination codons on FXI mRNA metabolism.