Molecular Basis of Inherited Defect of Antithrombin in Ten CzechFamilies
MOLEKULÁRNÍ PODSTATA VROZENÉHO DEFEKTUANTITROMBINU U DESETI EESKÝCH RODIN
Východisko.
Molekulárni genetická podstata vrozeného defektu antitrombinu (AT) nebyla v Eeské republicedosud studována. Hledali jsme kauzální mutace v rozsahu celého genu antitrombinu u souboru 26 nemocných z 10zjevni nepoíbuzných rodin.Metody a výsledky. Pomocí konformaeni senzitivní gelové elektrofézy (CSGE) byly identifikovány exonys abnormální sekvencí. Abnormální amplikony byly sekvenovány pomocí fluorescenení technologie k charakterizacimutací a polymorfizmu. Mutace byly nalezeny u všech deseti rodin. Identifikovali jsme následující etyoi dosudnepopsané mutace u etyo rodin s defektem antitrombinu typu I: Trp-6Arg, 5386-5387delCT, Glu163Stop, 13246-13248del TGA zpusobující deleci Glu377 a záminu Asn376Lys. U zbylých toí rodin s defektem typu I bylyidentifikovány následující již známé mutace: zámina G2777C v sestoihovém místi, Arg197Stop a delece celéhogenu. V rodini s Trp-6Arg byl navíc prokázán AT-Vídeo (Gln118Pro). Mutace Leu99Phe, eastá v jihovýchodníEvropi, byla nalezena u toí zjevni nepoíbuzných rodin s defektem typu II. Pouze homozygotní jedinci byli sympto-matietí poesto, že i heterozygotní jedinci vykazovali sníženou funkení hladinu antitrombinu.Závir. Identifikovali jsme 4 nové mutace u rodin s deficitem antitrombinu typu I. V jedné rodini jsme nalezli dvaruzné genetické defekty spojené s fenotypy typu I a II. Celkovi naše výsledky potvrzují heterogenitu mutacíu nemocných s vrozeným defektem antitrombinu.
Klíčová slova:
antitrombin, mutace, gen, trombóza, heparin.
Authors:
I. Hrachovinová; D. Habart; P. Salaj; M. Matýšková
Authors‘ workplace:
Ústav hematologie a krevní transfuze, Praha 1 Oddilení klinické hematologie FNsP, Brno-Bohunice
Published in:
Čas. Lék. čes. 2000; : 595-597
Category:
Overview
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.
Labels
Addictology Allergology and clinical immunology Angiology Audiology Clinical biochemistry Dermatology & STDs Paediatric gastroenterology Paediatric surgery Paediatric cardiology Paediatric neurology Paediatric ENT Paediatric psychiatry Paediatric rheumatology Diabetology Pharmacy Vascular surgery Pain management Dental HygienistArticle was published in
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