Bayston, TA; Tripodi, A; Mannucci, PM; Thompson, E; Ireland, H; Fitches, AC; ... Lane, DA; + view all Bayston, TA; Tripodi, A; Mannucci, PM; Thompson, E; Ireland, H; Fitches, AC; Hananeia, L; Olds, RJ; Lane, DA; - view fewer (1999) Familial overexpression of beta antithrombin caused by an Asn135Thr substitution. BLOOD , 93 (12) 4242 - 4247.
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We have investigated the basis of antithrombin deficiency in an asymptomatic individual (and family) with borderline levels (approximate to 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 (approximate to 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. (C) 1999 by The American Society of Hematology.
|Title:||Familial overexpression of beta antithrombin caused by an Asn135Thr substitution|
|Keywords:||THROMBOSIS-AND-HEMOSTASIS, STANDARDIZATION COMMITTEE, INHIBITORS SUBCOMMITTEE, MUTATION DATABASE, HEPARIN AFFINITY, DEFICIENCY, VARIANT, ASN-135, ISOFORM, INVIVO|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science|
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