The Molecular Basis of Antithrombin Deficiency in Belgian and Dutch Families

K. Jochmans; W. Lissens; S. Seneca; P. Capel; B. Chatelain; P. Meeus; J. C. Osselaer; K. Peerlinck; J. Seghers; M. Slacmeulder; J. Stibbe; J. van de Loo; J. Vermylen; I. Liebaers; M. De Waele

doi:10.1055/s-0037-1615215

Thrombosis and Haemostasis, Table of Contents

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

¹From the Departments of Hematology and Medical Genetics, Academic Hospital Free University Brussels, Belgium

,

W. Lissens

²From the Departments of Medical Genetics, Academic Hospital Free University Brussels, Belgium

,

S. Seneca

²From the Departments of Medical Genetics, Academic Hospital Free University Brussels, Belgium

,

P. Capel

³From the Departments of University Hospital Erasme ULB, Brussels, Belgium

,

B. Chatelain

⁴From the Departments of University Hospital UCL, Mont-Godinne, Belgium

,

P. Meeus

⁵From the Departments of OLV Ziekenhuis, Aalst, Belgium

,

J. C. Osselaer

⁴From the Departments of University Hospital UCL, Mont-Godinne, Belgium

,

K. Peerlinck

⁶From the Departments of Center for Molecular and Vascular Biology, University of Leuven, Belgium

,

J. Seghers

⁷From the Departments of Centre Hospitalier du Grand Hornu, Belgium

,

M. Slacmeulder

⁸From the Departments of University Hospital Dijkzigt, Rotterdam, The Netherlands

,

J. Stibbe

⁸From the Departments of University Hospital Dijkzigt, Rotterdam, The Netherlands

,

J. van de Loo

⁹From the Departments of St. Jansziekenhuis, Weert, The Netherlands

,

J. Vermylen

⁶From the Departments of Center for Molecular and Vascular Biology, University of Leuven, Belgium

,

I. Liebaers

²From the Departments of Medical Genetics, Academic Hospital Free University Brussels, Belgium

,

M. De Waele

¹From the Departments of Hematology and Medical Genetics, Academic Hospital Free University Brussels, Belgium

› Author Affiliations

Abstract

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.

Full Text

References

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