deficiency A classification system for cross-reactive material negative factor XI

ABSTRACT: The bleeding disorder associated with factor XI (fXI) deficiency is typically inherited as an autosomal recessive trait. However, some fXI mutations may be associated with dominant disease transmission. FXI is a homodimer, a feature that could allow certain mutations to exert a dominant negative effect on wild type fXI secretion through heterodimer formation. We describe two novel fXI mutations (Ser225Phe and Cys398Tyr) that form intracellular dimers, are secreted poorly, and exhibit dominant negative effects on wild type fXI secretion in co-transfection experiments. Available data now suggest that mutations associated with cross reactive material negative fXI deficiency fall into one of three mechanistic categories: (1) mutations that reduce or prevent polypeptide synthesis, (2) polypeptides that fail to form intracellular dimers and are retained in cells as monomers, and (3) polypeptides that form dimers that are not secreted. The latter category likely accounts for many cases of dominant disease transmission. From bloodjournal.hematologylibrary.org by guest on June 3, 2013. For personal use only.