A G>A Transition in the Non-Coding Exon 1 of the Factor XI Gene as the Cause of Factor XI Deficiency in Three Afro-Caribbean Patients.

Factor XI deficiency (MIM 264900) is an autosomal bleeding disorder of variable clinical severity. In contrast to haemophilia A or B the clinical symptoms do not correlate well with plasma levels of factor XI; it is therefore difficult to predict the bleeding tendency from either the factor level or the molecular defect. FXI deficiency is particularly common in the Ashkenazi Jews with a heterozygous frequency of 9%, associated with two common founder mutations E117X (Type II) and F283L (Type III). However, factor XI deficiency is found in all ethnic groups, with causative mutations being highly heterogeneous - mutations having been described in all exons with the exception of the non-coding exon 1.

In a study of >120 ethnically diverse factor XI deficient patients, three patients of Afro-Caribbean origin were found to be heterozygous for a G>A transition at nucleotide −53 within exon 1 of the factor XI gene. All three patients showed a low FXI:C on at least 3 different occasions (SM[female] 44.3–57.1, AB[female] 42.3–51.2 and GA[male] 70.3–72.9, Range 76–136u/dl). The 2 female patients were both reported to have a lupus anticoagulant which may explain the lower levels seen, although a lupus screen was negative. No variation within the coding sequence of the factor XI gene was detected. Two of the patients were heterozygous for the −403 G>T promoter polymorphism, whilst the remaining patient was homozygous for the −403 T allele and heterozygous for the −273 C>G polymorphism. Analysis of >50 factor XI alleles in patients of Afro-Caribbean origin failed to detect this base change in individuals with normal factor XI levels.

Purine-rich sequences, such as that in exon 1 affected by the −53 G>A substitution, are known to form extremely stable minihairpin loops. These sequences /structures have been shown to be important as splicing enhancers and in mRNA stability, particularly in making them more resistant to nucleases. Within the 5′ untranslated region (5′-UTR) of genes they have been demonstrated to be important in modulating translation efficiency. The -53 G>A substitution is located just 10 bases prior to the start of the factor XI mRNA and any of these mechanism could potentially explain the causative nature of this change. The -53 G>A substitution is predicted to cause ‘slippage’ within the postulated minihairpin loop, potentially making it unstable. Further work is on-going to try and prove and explain the causality of this mutation.

We speculate that the -53 G>A base change affects the normal processing of factor XI mRNA and, possibly in combination with the promoter polymorphisms, results in a mildly reduced plasma factor XI level.