NEW SPLICING MUTATIONS IN THE HUMAN FACTOR XIIIA GENE, EACH PRODUCINGMULTIPLE MUTANT TRANSCRIPTS OF VARYING ABUNDANCE

Coagulation factor XIII, a transglutaminase which stabilises blood clo ts by covalently cross-linking fibrin, is essential for normal haemost asis. FXIII deficiency results in a life-long bleeding disorder with a dded complications in wound healing and tissue repair. Sequence change s in the human FXIIIA gene, largely missense mutations, are primarily responsible for inherited FXIIl deficiency. We have carried out molecu lar analysis of the FXIIIA gene in two unrelated FXIII deficient indiv iduals and identified three splice site mutations; a g-ta at the exon 6 acceptor splice site, a g-->a at the exon 7 donor splice site and a coding sequence T-->G at the exon 8 donor splice site. We have also ex amined the FXIIIA mRNA in these patients and find that each mutation g ives rise to multiple transcripts which vary in their relative abundan ce. The precise molecular mechanisms which result in these variant tra nscripts, and their relative abundance in our FXIII deficient patients , are discussed.