Mutations affecting the cytoplasmic functions of the co-chaperone DNAJB6 cause limb-girdle muscular dystrophy
| العنوان: | Mutations affecting the cytoplasmic functions of the co-chaperone DNAJB6 cause limb-girdle muscular dystrophy |
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| المؤلفون: | Sara Lehtinen, Peter Hackman, Enzo Ricci, Jeffrey M. Stajich, Johanna Palmio, Jaakko Sarparanta, Per Harald Jonson, Satu Sandell, Sini Penttilä, Sanna Huovinen, Mark Screen, Olayinka Raheem, Bjarne Udd, Giorgio Tasca, Christelle Golzio, Nicholas Katsanis, Anna Vihola, Michael A. Hauser, Ibrahim Mahjneh, Kristin K. McDonald, H. Luque |
| المصدر: | Nature genetics |
| بيانات النشر: | Springer Science and Business Media LLC, 2012. |
| سنة النشر: | 2012 |
| مصطلحات موضوعية: | Gene isoform, Genotype, Mutation, Missense, Nerve Tissue Proteins, BAG3, Article, 03 medical and health sciences, 0302 clinical medicine, Genetics, medicine, Animals, Humans, Missense mutation, Muscular dystrophy, Muscle, Skeletal, Zebrafish, Finland, Adaptor Proteins, Signal Transducing, 030304 developmental biology, 0303 health sciences, biology, HSP40 Heat-Shock Proteins, biology.organism_classification, medicine.disease, United States, Italy, Muscular Dystrophies, Limb-Girdle, Chaperone (protein), biology.protein, Apoptosis Regulatory Proteins, 030217 neurology & neurosurgery, Molecular Chaperones, Limb-girdle muscular dystrophy |
| الوصف: | Limb-girdle muscular dystrophy type 1D (LGMD1D) was linked to chromosome 7q36 over a decade ago, but its genetic cause has remained elusive. Here we studied nine LGMD-affected families from Finland, the United States and Italy and identified four dominant missense mutations leading to p.Phe93Leu or p.Phe89Ile changes in the ubiquitously expressed co-chaperone DNAJB6. Functional testing in vivo showed that the mutations have a dominant toxic effect mediated specifically by the cytoplasmic isoform of DNAJB6. In vitro studies demonstrated that the mutations increase the half-life of DNAJB6, extending this effect to the wild-type protein, and reduce its protective anti-aggregation effect. Further, we show that DNAJB6 interacts with members of the CASA complex, including the myofibrillar myopathy-causing protein BAG3. Our data identify the genetic cause of LGMD1D, suggest that its pathogenesis is mediated by defective chaperone function and highlight how mutations in a ubiquitously expressed gene can exert effects in a tissue-, isoform- and cellular compartment-specific manner. |
| تدمد: | 1546-1718 1061-4036 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::dc2ba5f0889768ff195465015e1a0879Test https://doi.org/10.1038/ng.1103Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....dc2ba5f0889768ff195465015e1a0879 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15461718 10614036 |
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