title: A knock-in mouse model for the R120G mutation of αB-crystallin recapitulates human hereditary myopathy and cataracts.
abstract: 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.
authors: Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, Missouri, United States of America. andley@vision.wustl.edu
authors: Usha P
authors: UP
authors: Andley
authors: Paul D
authors: PD
authors: Hamilton
authors: Nathan
authors: N
authors: Ravi
authors: Conrad C
authors: CC
authors: Weihl
mesh_terms: D000818:Animals; D002386:Cataract / Q000235:genetics*; D003459:Crystallins / Q000235:genetics*; D004195:Disease Models, Animal; D055879:Gene Knock-In Techniques; D020022:Genetic Predisposition to Disease; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D009135:Muscular Diseases / Q000235:genetics*; D009154:Mutation
chemical_list: D003459:Crystallins