Molecular genetics of J-domain protein-related chaperonopathies in skeletal muscle.

IF 2.5 3区 生物学 Q2 GENETICS & HEREDITY
Michio Inoue
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引用次数: 0

Abstract

The J-domain proteins (JDPs), or HSP40s, are essential molecular co-chaperones that, in concert with HSP70, play a pivotal role in maintaining protein homeostasis, which is particularly critical in skeletal muscle. In recent years, pathogenic variants in several JDP-encoding genes have been identified as a cause of a growing group of inherited muscle diseases, termed JDP-related myopathies. This review provides a comprehensive overview of the current understanding of the molecular genetics, clinical phenotypes, muscle pathology, and pathomechanisms of myopathies caused by mutations in DNAJB6, DNAJB4, and DNAJB2. These disorders present with a wide spectrum of clinical features, including limb-girdle or distal weakness, and, in some cases, severe early-onset respiratory failure with axial rigidity. Pathologically, they are often characterized by rimmed vacuoles and sarcoplasmic protein inclusions. The underlying molecular mechanisms all involve disruption of the JDP-HSP70 chaperone system, but they are driven by distinct molecular events specific to each gene and mutation type. While loss-of-function is a primary mechanism for recessive forms of DNAJB4 and DNAJB2 myopathy, a toxic gain-of-function mediated by a dysregulated interaction with HSP70 is emerging as a central pathomechanism for dominant myopathies caused by DNAJB6 and DNAJB4 variants. A dominant-negative effect is proposed for dominant DNAJB2 neuromyopathy. This evolving mechanistic understanding is crucial as it informs the development of targeted therapeutic strategies, moving beyond supportive care. Potential future therapies include gene replacement for loss-of-function disorders, and for gain-of-function diseases, approaches including small molecule inhibitors of the JDP-HSP70 interaction or allele- and isoform-specific knockdown.

骨骼肌j结构域蛋白相关伴侣病的分子遗传学研究。
j结构域蛋白(jdp)或hsp40是必不可少的分子共伴侣,与HSP70一起,在维持蛋白质稳态中起关键作用,这在骨骼肌中尤为重要。近年来,几个jdp编码基因的致病变异已被确定为越来越多的遗传性肌肉疾病(称为jdp相关肌病)的原因。本文综述了目前对DNAJB6、DNAJB4和DNAJB2突变引起的肌病的分子遗传学、临床表型、肌肉病理和病理机制的理解。这些疾病表现出广泛的临床特征,包括四肢带或远端无力,在某些情况下,严重的早发性呼吸衰竭伴轴向僵硬。病理上常表现为边缘空泡和肌浆蛋白包涵体。潜在的分子机制都涉及JDP-HSP70伴侣系统的破坏,但它们是由每个基因和突变类型特有的不同分子事件驱动的。虽然功能丧失是隐性形式DNAJB4和DNAJB2肌病的主要机制,但由与HSP70的失调相互作用介导的毒性功能获得正在成为由DNAJB6和DNAJB4变体引起的显性肌病的中心病理机制。显性DNAJB2神经肌病存在显性-负性效应。这种不断发展的机制理解是至关重要的,因为它为有针对性的治疗策略的发展提供了信息,而不仅仅是支持性治疗。潜在的未来治疗方法包括功能丧失疾病的基因替代和功能获得疾病的基因替代,包括JDP-HSP70相互作用的小分子抑制剂或等位基因和异构体特异性敲除。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of Human Genetics
Journal of Human Genetics 生物-遗传学
CiteScore
7.20
自引率
0.00%
发文量
101
审稿时长
4-8 weeks
期刊介绍: The Journal of Human Genetics is an international journal publishing articles on human genetics, including medical genetics and human genome analysis. It covers all aspects of human genetics, including molecular genetics, clinical genetics, behavioral genetics, immunogenetics, pharmacogenomics, population genetics, functional genomics, epigenetics, genetic counseling and gene therapy. Articles on the following areas are especially welcome: genetic factors of monogenic and complex disorders, genome-wide association studies, genetic epidemiology, cancer genetics, personal genomics, genotype-phenotype relationships and genome diversity.
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