Major Structural Defects in the Antithrombin Gene in Four Families with Type I Antithrombin Deficiency

N. J. Beauchamp; M. Makris; F. E. Preston; I. R. Peake; M. E. Daly

doi:10.1055/s-0037-1613898

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2000; 83(05): 715-721
DOI: 10.1055/s-0037-1613898

Review Article

Schattauer GmbH

Major Structural Defects in the Antithrombin Gene in Four Families with Type I Antithrombin Deficiency

Partial/complete Deletions and Rearrangement of the Antithrombin Gene

N. J. Beauchamp

¹From the Division of Molecular and Genetic Medicine, University of Sheffield Faculty of Medicine Royal Hallamshire Hospital, Sheffield, United Kingdom

,

M. Makris

¹From the Division of Molecular and Genetic Medicine, University of Sheffield Faculty of Medicine Royal Hallamshire Hospital, Sheffield, United Kingdom

,

F. E. Preston

¹From the Division of Molecular and Genetic Medicine, University of Sheffield Faculty of Medicine Royal Hallamshire Hospital, Sheffield, United Kingdom

,

I. R. Peake

¹From the Division of Molecular and Genetic Medicine, University of Sheffield Faculty of Medicine Royal Hallamshire Hospital, Sheffield, United Kingdom

,

M. E. Daly

¹From the Division of Molecular and Genetic Medicine, University of Sheffield Faculty of Medicine Royal Hallamshire Hospital, Sheffield, United Kingdom

› Author Affiliations

Abstract

Summary

The molecular basis of quantitative antithrombin deficiency was investigated in four families predicted to have major antithrombin gene rearrangements. A 1,442 bp deletion and insertion of the sequence 5’T_{(n = 38-40)}GAGACG was characterised in one case. Sequence surrounding the breakpoints contained two perfect, and one imperfect, inverted repeats which may have mediated formation of a stem loop structure on one strand during DNA replication potentiating the deletion. A 9,219 bp deletion spanning introns 2 to 5 was identified in a second family. The identical 6 bp sequence was upstream of each breakpoint and the 5’ breakpoint was located in a sequence of the Alu 3 repeat predicted to be susceptible to strand breakage during transcription. This may have promoted misalignment, and deletion, of one of the repeats and the intervening DNA. A novel 1.8 kb antithrombin gene fragment was present in DNA digests from affected members of the third family suggesting a partial antithrombin gene duplication event while in the remaining family, evidence supporting a complete gene deletion was obtained.

Keywords

Antithombin deficiency - major gene defects

Full Text

References

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