Antithrombin Mutation Database
THE ANTITHROMBIN MOLECULE
Antithrombin is a plasma inhibitor of thrombin and other blood coagulation proteinases. Its (functional) deficiency is a strong risk factor for venous thrombosis. The gene coding for antithrombin has been localised to chromosome 1q23-25. The nucleotide sequence is available from the US National Center for Biotechnology Information. A single copy has seven exons spanning 13.4 kb of DNA. Within the introns of the gene are located nine full length and one partial Alu repeat elements, see Figure. Two of these Alu5 and Alu8 within intron 4 have tails composed of ATT trinucleotide repeats that are polymorphic in copy number (for gene sequence of anthrombin, see Olds et al, 1993). The gene codes for a protein of MW ~58 000 containing 432 amino acids, 6 of which are cysteines that form three intramolecular disulphide bonds. Antithrombin is a member of a superfamily of proteins collectively known as serine proteinase inhibitors (serpins). Most of the members of this family are inhibitors that control proteolysis of key blood cellular and tissue enzymes. The crystal structures of several members of this family have been determined and these structures have aided understanding of the mechanism of action of the serpins, including antithrombin (for a recent review of serpin structures, see Whisstock et al,1998). Antithrombin contains a functional reactive site which participates in the inhibitory interaction with proteinases, but also a binding site for heparin and related glycosaminoglycans. Binding of heparin to the latter site induces a conformational change and accelerates its inhibition of proteinases (see for example Desai et al, 1998; Huntington & Gettins, 1998). The nature of the heparin binding site on antithrombin has been investigated initially by chemical modification, by investigation of natural and recombinant mutants, and recently by high resolution crystallography (see Jin et al, 1997).
The natural mutants of antithrombin, mostly identified from families with a tendency towards thrombosis, are collected together in this database which has been published conventionally (Lane et al, 1991) and recently updated (Lane et al, 1993; Lane et al, 1997). This database is compiled by members of the Plasma Coagulation Inhibitors Subcommittee of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis (SSC of the ISTH). The final version of the database was put together by Trevor Bayston and David Lane. It was reformatted for the web by Malcolm Duncan (Medical Object Oriented Software Enterprises) and Helen Philippou, David Lane (Department of Haematology, Imperial College School of Medicine, Charing Cross Hospital Campus, Hammersmith, London, UK).
The naming convention accords with "Recommendations for a Nomenclature System for Human Gene Mutations" (see Antonarakis et al, 1998), except that the nucleotide numbering of the original database has been retained (see Olds et al,1993 and Lane et al, 1997). Each entry has been assigned a unique identifier on the basis of the subclass and position in the table for its subclass (e.g. type I case 11 has the mutation 2606insT). The identified mutations are grouped according to a classification system proposed (Lane et al, 1992) and accepted by the SSC of the ISTH. In this, type I and type II deficiencies are distinguished, largely by the presence of variant protein in the latter. Then type II deficiency is further subclassified on the basis of mutations that alter the function of the reactive site, the heparin binding site, and those that have multiple or pleiotropic effects. The database will be periodically updated, depending on the rate at which new mutations are identified. To have mutations included, send information in the format given in the tables to firstname.lastname@example.org