Musculoskeletal Research, Murdoch Children's Research Institute, Royal Children's Hospital, Parkville Victoria, Australia.
Department of Paediatrics, University of Melbourne, Parkville Victoria, Australia.
Anat Rec (Hoboken). 2020 Jun;303(6):1527-1542. doi: 10.1002/ar.24086. Epub 2019 Mar 6.
Mutations in the genes for extracellular matrix (ECM) components cause a wide range of genetic connective tissues disorders throughout the body. The elucidation of mutations and their correlation with pathology has been instrumental in understanding the roles of many ECM components. The pathological consequences of ECM protein mutations depend on its tissue distribution, tissue function, and on the nature of the mutation. The prevalent paradigm for the molecular pathology has been that there are two global mechanisms. First, mutations that reduce the production of ECM proteins impair matrix integrity largely due to quantitative ECM defects. Second, mutations altering protein structure may reduce protein secretion but also introduce dominant negative effects in ECM formation, structure and/or stability. Recent studies show that endoplasmic reticulum (ER) stress, caused by mutant misfolded ECM proteins, makes a significant contribution to the pathophysiology. This suggests that targeting ER-stress may offer a new therapeutic strategy in a range of ECM disorders caused by protein misfolding mutations. Anat Rec, 2019. © 2019 The Authors. The Anatomical Record published by Wiley Periodicals, Inc. on behalf of American Association of Anatomists.
细胞外基质（ECM）成分基因的突变会导致全身范围内广泛的遗传性结缔组织疾病。阐明突变及其与病理学的相关性，对于理解许多 ECM 成分的作用至关重要。ECM 蛋白突变的病理后果取决于其组织分布、组织功能以及突变的性质。分子病理学的流行范例一直是存在两种全局机制。首先，减少 ECM 蛋白产生的突变会因定量 ECM 缺陷而严重损害基质完整性。其次，改变蛋白质结构的突变可能会减少蛋白质分泌，但也会在 ECM 的形成、结构和/或稳定性中引入显性负效应。最近的研究表明，内质网（ER）应激，由突变导致的错误折叠 ECM 蛋白引起，对病理生理学有重要贡献。这表明，针对 ER 应激可能为一系列由蛋白质错误折叠突变引起的 ECM 疾病提供新的治疗策略。解剖记录，2019. © 2019 作者。解剖记录由 Wiley 期刊出版公司代表美国解剖学家协会出版。
