Dominant factor XI deficiency caused by mutations in the factor XI catalytic domain.

Kravtsov DV, Wu W, Meijers JC, Sun MF, Blinder MA, Dang TP, Wang H, Gailani D
Blood. 2004 104 (1): 128-34

PMID: 15026311 · DOI:10.1182/blood-2003-10-3530

The bleeding diathesis associated with hereditary factor XI (fXI) deficiency is prevalent in Ashkenazi Jews, in whom the disorder appears to be an autosomal recessive condition. The homodimeric structure of fXI implies that the product of a single mutant allele could confer disease in a dominant manner through formation of heterodimers with wild-type polypeptide. We studied 2 unrelated patients with fXI levels less than 20% of normal and family histories indicating dominant disease transmission. Both are heterozygous for single amino acid substitutions in the fXI catalytic domain (Gly400Val and Trp569Ser). Neither mutant is secreted by transfected fibroblasts. In cotransfection experiments with a wild-type fXI construct, constructs with mutations common in Ashkenazi Jews (Glu117Stop and Phe283Leu) and a variant with a severe defect in dimer formation (fXI-Gly350Glu) have little effect on wild-type fXI secretion. In contrast, cotransfection with fXI-Gly400Val or fXI-Trp569Ser reduces wild-type secretion about 50%, consistent with a dominant negative effect. Immunoprecipitation of cell lysates confirmed that fXI-Gly400Val forms intracellular dimers. The data support a model in which nonsecretable mutant fXI polypeptides trap wild-type polypeptides within cells through heterodimer formation, resulting in lower plasma fXI levels than in heterozygotes for mutations that cause autosomal recessive fXI deficiency.

MeSH Terms (22)

Adult Amino Acid Substitution Animals Catalytic Domain Cell Line Coleoptera Dimerization Factor XI Factor XI Deficiency Fibroblasts Gene Expression Genes, Dominant Heterozygote Humans Intracellular Space Luciferases Male Middle Aged Pedigree Prekallikrein Recombinant Proteins Transfection

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