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The molecular basis of antithrombin deficiency in Belgian and Dutch families

par Jochmans, Kristin;De Waele, Marc;Lissens, Willy;Seneca, Sara;Liebaers, Ingeborg ;Capel, Paul ;Chatelain, Bernard;Osselaer, Jean Claude;Slacmeulder, Michel;Meeus, Peter;Peerlinck, Kathelijne M J K.;Vermylen, Jos;Seghers, J.;Stibbe, Jeanne;Van De Loo, Jürgen C W J.
Référence Thrombosis and haemostasis, 80, 3, page (376-381)
Publication Publié, 1998-09

Article révisé par les pairs

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Résumé :

The molecular basis of hereditary antithrombin (AT) deficiency has been investigated in ten Belgian and three Dutch unrelated kindreds. Eleven of these families had a quantitative or type I AT deficiency, with a history of major venous thromboembolic events in different affected members. In the other two families a qualitative or type II AT deficiency was occasionally diagnosed. DNA studies of the AT gene were performed, using polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) analysis, followed by direct sequencing of the seven exons and intron-exon junction regions. Six novel point mutations were identified: four missense, one nonsense mutation and a single nucleotide deletion near the reactive site, causing a frameshift with premature translation termination. In two kindreds the underlying genetic defect was caused by a whole gene deletion, known as a rare cause of AT deficiency. In these cases, Southern blot and polymorphism analysis of different parts of the AT gene proved useful for diagnosis. In another kindred a partial gene deletion spanning 698 basepairs could precisely be determined to a part of intron 3B and exon 4. In two type I and in both type II AT deficient families a previously reported mutation was identified. In all cases, the affected individuals were heterozygous for the genetic defect.