{"title":"Molecular genetics of J-domain protein-related chaperonopathies in skeletal muscle.","authors":"Michio Inoue","doi":"10.1038/s10038-025-01372-8","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":2.5000,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12360427/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Human Genetics","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1038/s10038-025-01372-8","RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}
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.
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.