Coagulation factor XI gene analysis in three factor XI deficient Austrian patients

Hereditary factor XI deficiency is a rare bleeding disorder with worldwide distribution. In Austrian patients only one mutation leading to congenital factor XI deficiency has been reported. In the present study, we identified the molecular basis of factor XI deficiency in three Austrian patients.

Patients attended hospital for other reasons than bleeding disorders. Routine laboratory tests revealed prolonged APTTs due to decreased factor XI levels. We performed automated fluorescent sequencing of the promotor region, exons 1-15 and the flanking intronic regions of the factor XI gene. The mutations found were confirmed by restriction enzyme analysis or sequencing of the non-coding strand.

Fluorescent sequencing revealed two novel mutations, the nonsense mutation Gln116X (443C>T) in exon 5 and a deletion of Ile197 and Asp198 (687_692delTCGACA) in exon 7. Furthermore, we detected a heterozygous A>G exchange at the third nucleotide of IVS6 (IVS 6 +3A>G), which had already been reported in a FXI deficient individual of French Basque origin.

While the IVS 6 +3A>G decreases the calculated splice consensus score from 0.98 in the wild type to 0.56 in the altered sequence and therefore interferes with the consensus splice sequence, the complete loss of the two amino acids Ile197 and Asp198 is expected to interfere with the steric structure and hence the functions of the third apple domain. The Gln116X leads to a premature termination codon resulting in a lack of the light as well as parts of the heavy chain of the FXI protein, most likely resulting in rapid degradation of the truncated mRNA.