title: Five antithrombin variants, four associated with thrombosis.
abstract: We have identified five mutations in antithrombin by direct sequencing of exons amplified using polymerase chain reaction. Four of these mutations are associated with thrombosis, three cause type I antithrombin deficiency and one has features of a type II deficiency. The fifth variant appears to have no functional consequences. The type I mutations are in exon 2, exon 3b and exon 4. The first of these is a nonsense mutation causing substitution of a Tyr-->stop at position -16 within the secretion signal sequence. The second is a missense mutation resulting in the substitution Cys-->Ser at position 247. This disrupts the disulphide bond with Cys 430 leaving a free cysteine residue and the C-terminus unconstrained. The third type I mutation is an in-frame deletion resulting in the loss of Ile 186. This is a highly conserved residue in the serpin superfamily and will predictably result in the disruption of the F-helix. The fourth mutation, in exon 3a, results in the substitution of Ser 162 by Asn. This residue is sited in the E-helix and the replacement of the buried side chain of serine by the larger asparagine side chain will predictably cause structural perturbation. The last example, Val 415-->Asp, was an incidental finding as a follow up investigation of a nephrotic patient. Although one other member of the family also had the mutation there was no linked history of thrombotic disease.
authors.affiliation: University of Cambridge Department of Haematology, UK.
authors.forename: H L
authors.initials: HL
authors.lastname: Fitton
authors.forename: I D
authors.initials: ID
authors.lastname: Walker
authors.forename: L
authors.initials: L
authors.lastname: Jones
authors.forename: K
authors.initials: K
authors.lastname: Brown
authors.forename: R W
authors.initials: RW
authors.lastname: Carrell
authors.forename: P
authors.initials: P
authors.lastname: Coughlin
mesh_terms: D000328:Adult; D000368:Aged; D000990:Antithrombin III / Q000235:genetics* / Q000302:isolation & purification; D005091:Exons; D005260:Female; D016368:Frameshift Mutation; D006801:Humans; D008297:Male; D008958:Models, Molecular; D016133:Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D013927:Thrombosis / Q000097:blood / Q000235:genetics*
chemical_list: D000990:Antithrombin III