Proposed mechanisms for CRM-negative fXI deficiency. FXI dimers and monomers within circles at the top of the figure represent intracellular protein, arrows indicate secretion, and FXI dimers below the arrows represent plasma fXI. The percentage of activity and antigen values shown are what would be expected, on average, for different mechanisms. Mutations in category 1 prevent or reduce synthesis of fXI polypeptide, and heterozygosity for such a mutation would not affect the product of the normal allele. Glu117Stop is the most common example from this group. Category 2 contains polypeptides that are synthesized but dimerize poorly, resulting in intracellular retention of monomers. Heterozygosity for this type of mutant would have little effect on secretion of product from the normal allele, because the mutant would dimerize poorly with wild-type polypeptide, and heterodimers that do form are secreted. The diagram shows the expected result for the most common mutation in this group, Phe283Leu, which has a partial defect in dimerization. Category 3 includes polypeptides that are synthesized and form dimers, but that are secreted poorly in homodimeric or heterodimeric forms. This category includes Ser225Phe and Cys398Tyr. The mutant polypeptide reduces wild-type fXI polypeptide secretion through formation of nonsecretable heterodimers (dominant-negative effect). Het indicates heterozygote; and Hom, homozygote for fXI gene mutation.