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 I 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.
Jochmans, Koen ; Lissens, W. ; Seneca, S ; Capel, P. ; Chatelain, Bernard ; et. al. The molecular basis of antithrombin deficiency in Belgian and Dutch families. In: Thrombosis and Haemostasis : international journal for vascular biology and medicine, Vol. 80, no. 3, p. 376-381 (1998)