Thromb Haemost 1998; 80(03): 376-381
DOI: 10.1055/s-0037-1615215
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The Molecular Basis of Antithrombin Deficiency in Belgian and Dutch Families

K. Jochmans
1   From the Departments of Hematology and Medical Genetics, Academic Hospital Free University Brussels, Belgium
,
W. Lissens
2   From the Departments of Medical Genetics, Academic Hospital Free University Brussels, Belgium
,
S. Seneca
2   From the Departments of Medical Genetics, Academic Hospital Free University Brussels, Belgium
,
P. Capel
3   From the Departments of University Hospital Erasme ULB, Brussels, Belgium
,
B. Chatelain
4   From the Departments of University Hospital UCL, Mont-Godinne, Belgium
,
P. Meeus
5   From the Departments of OLV Ziekenhuis, Aalst, Belgium
,
J. C. Osselaer
4   From the Departments of University Hospital UCL, Mont-Godinne, Belgium
,
K. Peerlinck
6   From the Departments of Center for Molecular and Vascular Biology, University of Leuven, Belgium
,
J. Seghers
7   From the Departments of Centre Hospitalier du Grand Hornu, Belgium
,
M. Slacmeulder
8   From the Departments of University Hospital Dijkzigt, Rotterdam, The Netherlands
,
J. Stibbe
8   From the Departments of University Hospital Dijkzigt, Rotterdam, The Netherlands
,
J. van de Loo
9   From the Departments of St. Jansziekenhuis, Weert, The Netherlands
,
J. Vermylen
6   From the Departments of Center for Molecular and Vascular Biology, University of Leuven, Belgium
,
I. Liebaers
2   From the Departments of Medical Genetics, Academic Hospital Free University Brussels, Belgium
,
M. De Waele
1   From the Departments of Hematology and Medical Genetics, Academic Hospital Free University Brussels, Belgium
› Author Affiliations
Further Information

Publication History

Received 23 December 1997

Accepted after revision 07 May 1998

Publication Date:
08 December 2017 (online)

Summary

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 intronexon 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.

 
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