Major structural defects in the antithrombin gene in four families with type I antithrombin deficiency--partial/complete deletions and rearrangement of the antithrombin gene.
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.
Beauchamp
N J
NJ
Division of Molecular and Genetic Medicine, University of Sheffield Faculty of Medicine, Royal Hallamshire Hospital, United Kingdom.
Makris
M
M
Preston
F E
FE
Peake
I R
IR
Daly
M E
ME
D000293:Adolescent; D000328:Adult; D000990:Antithrombin III / Q000235:genetics*; D020152:Antithrombin III Deficiency / Q000145:classification / Q000150:complications / Q000235:genetics*; D001483:Base Sequence; D004252:DNA Mutational Analysis; D005260:Female; D017353:Gene Deletion; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D016133:Polymerase Chain Reaction; D012091:Repetitive Sequences, Nucleic Acid; D017384:Sequence Deletion; D019851:Thrombophilia / Q000150:complications / Q000235:genetics; D020246:Venous Thrombosis / Q000209:etiology
D000990:Antithrombin III