Amelioration of the severity of heparin-binding antithrombin mutations by posttranslational mosaicism

作者：Martinez Martinez Irene; Navarro Fernandez Jose; Ostergaard Alice; Gutierrez Gallego Ricardo; Padilla Jose; Bohdan Nataliya; Minano Antonia; Pascual Cristina; Martinez Constantino; Eugenia de la Morena Barrio Maria; Aguila Sonia; Pedersen Shona; Risom Kristensen Soren; Vicente Vicente; Corral Javier^*

来源：Blood, 2012, 120(4): 900-904.

DOI：10.1182/blood-2012-01-406207

The balance between actions of procoagulant and anticoagulant factors protects organisms from bleeding and thrombosis. Thus, antithrombin deficiency increases the risk of thrombosis, and complete quantitative deficiency results in intrauterine lethality. However, patients homozygous for L99F or R47C antithrombin mutations are viable. These mutations do not modify the folding or secretion of the protein, but abolish the glycosaminoglycan-induced activation of antithrombin by affecting the heparin-binding domain. We speculated that the natural beta-glycoform of antithrombin might compensate for the effect of heparin-binding mutations. We purified alpha- and beta-antithrombin glycoforms from plasma of 2 homozygous L99F patients. Heparin affinity chromatography and intrinsic fluorescence kinetic analyses demonstrated that the reduced heparin affinity of the alpha-L99F glycoform (K-D, 107.9 +/- 3nM) was restored in the beta-L99F glycoform (K-D, 53.9 +/- 5nM) to values close to the activity of alpha-wild type (K-D, 43.9 +/- 0.4nM). Accordingly, the beta-L99F glycoform was fully activated by heparin. Similar results were observed for recombinant R47C and P41L, other heparin-binding antithrombin mutants. In conclusion, we identified a new type of mosaicism associated with mutations causing heparin-binding defects in antithrombin. The presence of a fully functional beta-glycoform together with the activity retained by these variants helps to explain the viability of homozygous and the milder thrombotic risk of heterozygous patients with these specific antithrombin mutations. (Blood. 2012;120(4):900-904)

• 出版日期2012-7-26