A Knock-In Mouse Model for the R120G Mutation of αB-Crystallin Recapitulates Human Hereditary Myopathy and Cataracts
| العنوان: | A Knock-In Mouse Model for the R120G Mutation of αB-Crystallin Recapitulates Human Hereditary Myopathy and Cataracts |
|---|---|
| المؤلفون: | Paul D. Hamilton, Conrad C. Weihl, Nathan Ravi, Usha P. Andley |
| المصدر: | PLoS ONE, Vol 6, Iss 3, p e17671 (2011) PLoS ONE |
| بيانات النشر: | Public Library of Science (PLoS), 2011. |
| سنة النشر: | 2011 |
| مصطلحات موضوعية: | Pathology, Cataracts and Other Lens Disorders, Mutant, lcsh:Medicine, Vimentin, Biochemistry, Mice, 0302 clinical medicine, Missense mutation, Gene Knock-In Techniques, lcsh:Science, Intermediate filament, Liquid Chromatography, Chromatography, 0303 health sciences, Multidisciplinary, Neuromuscular Diseases, Chemistry, medicine.anatomical_structure, Neurology, Medicine, medicine.symptom, Research Article, medicine.medical_specialty, Biology, Cataract, 03 medical and health sciences, Muscular Diseases, Crystallin, Column Chromatography, Genetics, medicine, Animals, Humans, Genetic Predisposition to Disease, Myopathy, 030304 developmental biology, Size Exclusion Chromatography, lcsh:R, Proteins, Skeletal muscle, Crystallins, Molecular biology, Mice, Mutant Strains, eye diseases, Ophthalmology, Disease Models, Animal, Mutation, biology.protein, lcsh:Q, Desmin, sense organs, 030217 neurology & neurosurgery |
| الوصف: | An autosomal dominant missense mutation in αB-crystallin (αB-R120G) causes cataracts and desmin-related myopathy, but the underlying mechanisms are unknown. Here, we report the development of an αB-R120G crystallin knock-in mouse model of these disorders. Knock-in αB-R120G mice were generated and analyzed with slit lamp imaging, gel permeation chromatography, immunofluorescence, immunoprecipitation, histology, and muscle strength assays. Wild-type, age-matched mice were used as controls for all studies. Both heterozygous and homozygous mutant mice developed myopathy. Moreover, homozygous mutant mice were significantly weaker than wild-type control littermates at 6 months of age. Cataract severity increased with age and mutant gene dosage. The total mass, precipitation, and interaction with the intermediate filament protein vimentin, as well as light scattering of αB-crystallin, also increased in mutant lenses. In skeletal muscle, αB-R120G co-aggregated with desmin, became detergent insoluble, and was ubiquitinated in heterozygous and homozygous mutant mice. These data suggest that the cataract and myopathy pathologies in αB-R120G knock-in mice share common mechanisms, including increased insolubility of αB-crystallin and co-aggregation of αB-crystallin with intermediate filament proteins. These knock-in αB-R120G mice are a valuable model of the developmental and molecular biological mechanisms that underlie the pathophysiology of human hereditary cataracts and myopathy. |
| تدمد: | 1932-6203 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::fb74af5172e8d89af67d72eccb5b5adaTest https://doi.org/10.1371/journal.pone.0017671Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....fb74af5172e8d89af67d72eccb5b5ada |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 19326203 |
|---|