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

Kravtsov DV, Monahan PE, Gailani D
Blood. 2005 105 (12): 4671-3

PMID: 15728123 · PMCID: PMC1895004 · DOI:10.1182/blood-2004-05-1864

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 2 novel fXI mutations (Ser225Phe and Cys398Tyr) that form intracellular dimers, are secreted poorly, and exhibit dominant-negative effects on wild-type fXI secretion in cotransfection experiments. Available data now suggest that mutations associated with crossreactive material-negative fXI deficiency fall into 1 of 3 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.

MeSH Terms (23)

Adult Alleles Animals Blotting, Western Cell Line Cricetinae Dimerization DNA Exons Factor XI Factor XI Deficiency Female Fibroblasts Genes, Dominant Heterozygote Humans Male Models, Biological Mutation Peptides Point Mutation Sequence Analysis, DNA Transfection

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