Familial overexpression of β antithrombin caused by an Asn135Thr substitution

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

Research output: Contribution to journalArticle

Abstract

We have investigated the basis of antithrombin deficiency in an asymptomatic individual (and family) with borderline levels (≃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 β antithrombin (the very high affinity fraction) greatly increased (≃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 β antithrombin in regulating coagulation.

Original languageEnglish
Pages (from-to)4242-4247
Number of pages6
JournalBlood
Volume93
Issue number12
Publication statusPublished - Jun 15 1999

ASJC Scopus subject areas

  • Hematology

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    Bayston, T. A., Tripodi, A., Mannucci, P. M., Thompson, E., Ireland, H., Fitches, A. C., Hananeia, L., Olds, R. J., & Lane, D. A. (1999). Familial overexpression of β antithrombin caused by an Asn135Thr substitution. Blood, 93(12), 4242-4247.