Dominant factor XI deficiency caused by mutations in the factor XI catalytic domain
- 1 July 2004
- journal article
- case report
- Published by American Society of Hematology in Blood
- Vol. 104 (1), 128-134
- https://doi.org/10.1182/blood-2003-10-3530
Abstract
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.Keywords
This publication has 29 references indexed in Scilit:
- The Two Common Mutations Causing Factor XI Deficiency in Jews Stem From Distinct Founders: One of Ancient Middle Eastern Origin and Another of More Recent European OriginBlood, 1997
- Factor XI DeficiencyThrombosis and Haemostasis, 1993
- The coagulation cascade: initiation, maintenance, and regulationBiochemistry, 1991
- Factor XI Deficiency in Ashkenazi Jews in IsraelNew England Journal of Medicine, 1991
- Comparison of bleeding tendency, factor XI coagulant activity, and factor XI antigen in 25 factor XI-deficient kindredsBlood, 1985
- High gene frequency of factor XI (PTA) deficiency in Ashkenazi JewsBlood, 1978
- Heredity and Coagulation Studies in Ten Families with Factor XI (Plasma Thromboplastin Antecedent) DeficiencyBritish Journal of Haematology, 1965
- Clinical and laboratory studies of plasma thromboplastin antecedent deficiency (PTA)American Journal Of Medicine, 1960
- Plasma Thromboplastin Antecedent (PTA) DeficiencyArchives of Internal Medicine, 1957
- New Hemophilia-like Disease Caused by Deficiency of a Third Plasma Thromboplastin Factor.Experimental Biology and Medicine, 1953