Antithrombin Budapest 3 An antithrombin variant with reduced heparin affinity resulting from the substitution L99F

Olds, R.J.; Lane, David A.; Boisclair, Michael D.; Sas, G.; Bock, Susan; Thein, S L

doi:10.1016/0014-5793(92)80854-a

Cited by 55 publications

(44 citation statements)

References 31 publications

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“…Ala404Asp, a substitution in the RCL with pleiotropic effects that alters interactions with both thrombin and heparin, 8 demonstrated statistically significant rescue, although the average time to occlusion was longer than wild-type AT3. Leu99Phe, 50,51 identified in patients with venous thromboembolism, demonstrated rescue consistent with wild-type AT3, as did another heparin-binding mutant Lys114Glu. 52,53 The fact that heparin binding appears disposable was surprising, but consistent with human clinical data.…”

Section: Discussionmentioning

confidence: 82%

Targeted mutagenesis of zebrafish antithrombin III triggers disseminated intravascular coagulation and thrombosis, revealing insight into function

Liu¹,

Kretz

Maeder

et al. 2014

Blood

108

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Section: Discussionmentioning

confidence: 82%

Targeted mutagenesis of zebrafish antithrombin III triggers disseminated intravascular coagulation and thrombosis, revealing insight into function

Liu¹,

Kretz

Maeder

et al. 2014

Blood

108

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show abstract

“…An antithrombin heparin binding site has been proposed on the basis of genetic data (18,(49)(50)(51)(52)(53)(54)(55)(56)(57)(58), together with information from chemical modification experiments (59)(60)(61) and the properties of the glycosylation isoform, antithrombin-f3 (62,63). It consists of a surface ofhigh positive charge density around helix D and the NH2-terminal sequence of antithrombin which is not present on other serpins.…”

Section: -']-'----mentioning

confidence: 99%

Pleiotropic effects of antithrombin strand 1C substitution mutations.

Lane

Olds²,

Conard³

et al. 1992

J. Clin. Invest.

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Six different substitution mutations were identified in four different amino acid residues of antithrombin strand 1C and the polypeptide leading into strand 4B (F402S, F402C, F402L, A404T, N405K, and P407T), and are responsible for functional antithrombin deficiency in seven independently ascertained kindreds (Rosny, Torino, Maisons-Laffitte, Paris 3, La Rochelle, Budapest 5, and Oslo) affected by venous thromboembolic disease. In all seven families, variant antithrombins with heparin-binding abnormalities were detected by crossed immunoelectrophoresis, and in six of the kindreds there was a reduced antigen concentration of plasma antithrombin. Two of the variant antithrombins, Rosny and Torino, were purified by heparin-Sepharose and immunoaffinity chromatography, and shown to have greatly reduced heparin cofactor and progressive inhibitor activities in vitro. The defective interactions of these mutants with thrombin may result from proximity of s1C to the reactive site, while reduced circulating levels may be related to siC proximity to highly conserved internal ft strands, which contain elements proposed to influence serpin turnover and intracellular degradation. In contrast, siC is spatially distant to the positively charged surface which forms the heparin binding site of antithrombin; altered heparin binding properties of siC variants may therefore reflect conformational linkage between the reactive site and heparin binding regions of the molecule. This work demonstrates that point mutations in and immediately adjacent to strand 1C have multiple, or pleiotropic, effects on this serpin, leading ultimately to failure of its regulatory function. (J.

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“…23 However, our study revealed a new heterogeneity. Subjects carrying antithrombin Murcia had two circulating mutant isoforms that displayed different biochemical and functional features.…”

Section: Discussionmentioning

confidence: 54%

Antithrombin Murcia (K241E) causing antithrombin deficiency: a possible role for altered glycosylation

Martínez‐Martínez¹,

Ordóñez²,

Navarro-Fernández³

et al. 2010

Haematologica

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Antithrombin Budapest 3 An antithrombin variant with reduced heparin affinity resulting from the substitution L99F

Cited by 55 publications

References 31 publications

Targeted mutagenesis of zebrafish antithrombin III triggers disseminated intravascular coagulation and thrombosis, revealing insight into function

Targeted mutagenesis of zebrafish antithrombin III triggers disseminated intravascular coagulation and thrombosis, revealing insight into function

Pleiotropic effects of antithrombin strand 1C substitution mutations.

Antithrombin Murcia (K241E) causing antithrombin deficiency: a possible role for altered glycosylation

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