title: Novel point mutations leading to type 1 antithrombin deficiency and thrombosis.
abstract: Direct sequencing of antithrombin III (AT) gene fragments specifically amplified by the polymerase chain reaction was utilized to identify the molecular basis of type 1 AT deficiency in two unrelated kindreds, both with thrombotic disease. Two novel point mutations were identified, deletion of a T from the second position of codon 81 in one propositus and insertion of a G in codon 424 in the second kindred. The AT 81(-T) frameshift mutation leads to a premature stop signal in codon 89, while the AT 424(+G) allele has a premature stop only one codon short of the normal gene. The latter mutation changes the eight carboxy terminal residues of AT, including 429Cys, and increases the proportion of polar amino acids in this region. We suggest that altered folding of the mutant protein may explain the AT deficiency.
authors.affiliation: Institute of Molecular Medicine, John Radcliffe Hospital, Oxford.
authors.forename: R J
authors.initials: RJ
authors.lastname: Olds
authors.forename: D A
authors.initials: DA
authors.lastname: Lane
authors.forename: H
authors.initials: H
authors.lastname: Ireland
authors.forename: G
authors.initials: G
authors.lastname: Leone
authors.forename: V
authors.initials: V
authors.lastname: De Stefano
authors.forename: M L
authors.initials: ML
authors.lastname: Wiesel
authors.forename: J P
authors.initials: JP
authors.lastname: Cazenave
authors.forename: S L
authors.initials: SL
authors.lastname: Thein
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D000990:Antithrombin III / Q000235:genetics; D020152:Antithrombin III Deficiency; D001483:Base Sequence; D002648:Child; D004247:DNA / Q000032:analysis*; D004252:DNA Mutational Analysis; D004277:DNA, Single-Stranded; D005091:Exons; D005260:Female; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D016133:Polymerase Chain Reaction; D015183:Restriction Mapping
chemical_list: D004277:DNA, Single-Stranded; D000990:Antithrombin III; D004247:DNA