دورية أكاديمية
أعرض في EDS

Functional analysis of two abnormal antithrombin proteins with different intracellular kinetics.

التفاصيل البيبلوغرافية
العنوان: Functional analysis of two abnormal antithrombin proteins with different intracellular kinetics.
المؤلفون: Imai Y; Department of Clinical Laboratory Science, Division of Health Sciences, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, Japan., Nagaya S; Department of Clinical Laboratory Science, Division of Health Sciences, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, Japan., Araiso Y; Department of Clinical Laboratory Science, Division of Health Sciences, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, Japan., Meguro-Horike M; Research Center for Experimental Modeling of Human Disease, Kanazawa University, Kanazawa, Ishikawa, Japan., Togashi T; Department of Clinical Laboratory Science, Division of Health Sciences, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, Japan., Horike SI; Research Center for Experimental Modeling of Human Disease, Kanazawa University, Kanazawa, Ishikawa, Japan., Kawasaki H; Department of Medical Neuroscience, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan., Morishita E; Department of Clinical Laboratory Science, Division of Health Sciences, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, Japan; Department of Hematology, Kanazawa University Hospital, Kanazawa, Ishikawa, Japan. Electronic address: eriko86@staff.kanazawa-u.ac.jp.
المصدر: Thrombosis research [Thromb Res] 2023 Oct; Vol. 230, pp. 18-26. Date of Electronic Publication: 2023 Aug 15.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Pergamon Press Country of Publication: United States NLM ID: 0326377 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1879-2472 (Electronic) Linking ISSN: 00493848 NLM ISO Abbreviation: Thromb Res Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Elmsford, N. Y., Pergamon Press.
مواضيع طبية MeSH: Antithrombin III Deficiency*/genetics , Venous Thrombosis*/genetics, Humans ; Antithrombins ; Antithrombin Proteins ; Antithrombin III/genetics
مستخلص: Introduction: Hereditary antithrombin (AT) deficiency type I causes venous thrombosis due to decreased levels of AT antigen in the blood. We identified one novel and one known abnormal variant in two unrelated Japanese families with venous thrombosis. In this study, we analyzed the mechanism by which these abnormal variants cause type I AT deficiency.
Materials and Methods: Wild-type and variant AT expression vectors were constructed and transiently expressed in human embryonic kidney 293 cells, and AT antigen levels and N-glycosylation of cell lysates and culture medium were evaluated by western blot analysis. Subcellular co-localization of AT was also examined using confocal microscopy, and chase experiments with cycloheximide and MG132 were performed to investigate the degradation pathway of AT variants.
Results: Genetic analysis identified a novel variant, c.613delC (p.Leu205Trpfs ⁎ 79), and the known variant c.283T>C (p.Tyr95His). These AT variants exhibited significantly reduced extracellular secretion compared with the wild-type; N-glycosylation of the AT protein was normal. Co-localization analysis suggested that the transport of these abnormal AT proteins to the Golgi apparatus was impaired. The c.613delC variant was degraded early by the proteasome, suggesting that the c.283T>C variant is stored in the endoplasmic reticulum (ER).
Conclusions: The AT variants identified here synthesize abnormal AT proteins that exhibit suppressed secretion and impaired transport from the ER to the Golgi apparatus. These results provide clues that could help elucidate the mechanism of type I AT deficiency and facilitate therapy development.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 Elsevier Ltd. All rights reserved.)
فهرسة مساهمة: Keywords: Antithrombin deficiency; Extracellular secretion; Genetic analysis; Kinetic analysis
المشرفين على المادة: 0 (Antithrombins)
0 (Antithrombin Proteins)
9000-94-6 (Antithrombin III)
تواريخ الأحداث: Date Created: 20230822 Date Completed: 20231002 Latest Revision: 20231012
رمز التحديث: 20231012
DOI: 10.1016/j.thromres.2023.08.010
PMID: 37607435
قاعدة البيانات: MEDLINE
الوصف
تدمد:1879-2472
DOI:10.1016/j.thromres.2023.08.010