MOLEKULÁRNÍ PODSTATA VROZENÉHO DEFEKTUANTITROMBINU U DESETI EESKÝCH RODIN

Molecular Basis of Inherited Defect of Antithrombin in Ten CzechFamilies

Background.
Molecular basis of antithrombin deficiency has not yet been studied in Czech Republic. We lookedfor the causal mutations throughout the antithrombin gene in 26 patients from 10 unrelated families with antithrombindefect.Methods and Results. We screened the gene by conformation sensitive gel electrophoresis and sequenced themismatched regions using fluorescend technology to characterise mutations and polymorphisms. Mutations weredetected in all ten families. Four novel mutations were identified in four families with type I antithrombin defect:Trp-6Arg, 5386-5387delCT, Glu163Stop, and 13246-13248del TGA causing deletion of Glu377 with change ofAsn376 to Lys. In other three type I families we found following mutations: splicing site mutation G2777C,Arg197Stop and entire gene deletion. In the family carrying Trp-6Arg mutation antithrombin Vienna (Gln118Pro) was alsodetected. Leu99Phe recurrent in south-eastern Europe was identified in three families with type II defect. Only the homozygouscarries of the mutation were symptomatic, although the heterozygous carries had decreased functional levels.Conclusions. Four novel mutations in families with type I antithrombin deficiency were characterised. In onefamily two different genetic defects were identified to be responsible for type I and II phenotypes. Altogether ourdata agree with the expected heterogeneity of the AT genetic defect.

Key words:
antithrombin, mutation, gene, thrombosis, heparin.