A Knock-In Mouse Model for the R120G Mutation of alpha B-Crystallin Recapitulates Human Hereditary Myopathy and Cataracts

作者：Andley Usha P^*; Hamilton Paul D; Ravi Nathan; Weihl Conrad C

来源：PLos One, 2011, 6(3): e17671.

DOI：10.1371/journal.pone.0017671

An autosomal dominant missense mutation in alpha B-crystallin (alpha B-R120G) causes cataracts and desmin-related myopathy, but the underlying mechanisms are unknown. Here, we report the development of an alpha B-R120G crystallin knock-in mouse model of these disorders. Knock-in alpha B-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 alpha B-crystallin, also increased in mutant lenses. In skeletal muscle, alpha B-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 alpha B-R120G knock-in mice share common mechanisms, including increased insolubility of alpha B-crystallin and co-aggregation of alpha B-crystallin with intermediate filament proteins. These knock-in alpha B-R120G mice are a valuable model of the developmental and molecular biological mechanisms that underlie the pathophysiology of human hereditary cataracts and myopathy.

• 出版日期2011-3-18