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Familial overexpression of beta-antithrombin caused by an Asn135-to-Thr substitution.

Bayston T.A., Tripodi A., Mannucci P.M., Thompson E., Ireland H., Fitches A.C., Hananeia L., Olds R.J., Lane D.A.

We have investigated the basis of antithrombin deficiency in an asymptomatic individual (and family) with borderline levels (approximately 70% antigen and activity) of antithrombin. Direct sequencing of amplified DNA showed a mutation in codon 135, AAC to ACC, predicting a heterozygous Asn135Thr substitution. This substitution alters the predicted consensus sequence for glycosylation, Asn-X-Ser, adjacent to the heparin interaction site of antithrombin. The antithrombin isolated from plasma of the proband by heparin-Sepharose chromatography contained amounts of beta antithrombin (the very high affinity fraction) greatly increased (approximately 20% to 30% of total) above the trace levels found in normals. Expression of the residue 135 variant in both a cell-free system and COS-7 cells confirmed altered glycosylation arising as a consequence of the mutation. Wild-type and variant protein were translated and exported from COS-7 cells with apparently equal efficiency, in contrast to the reduced level of variant observed in plasma of the affected individual. This case represents a novel cause of antithrombin deficiency, removal of glycosylation concensus sequence, and highlights the potentially important role of beta antithrombin in regulating coagulation.

Blood 93:4242-4247(1999) [PubMed] [Europe PMC]

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