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

Andley, Usha P ; Hamilton, Paul D ; Ravi, Nathan ; Weihl, Conrad C

PloS one, 2011-03, Vol.6 (3) [Periódico revisado por pares]

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  • Título:
    A Knock-In Mouse Model for the R120G Mutation of I-B-Crystallin Recapitulates Human Hereditary Myopathy and Cataracts
  • Autor: Andley, Usha P ; Hamilton, Paul D ; Ravi, Nathan ; Weihl, Conrad C
  • Assuntos: Animal models ; Cataracts ; Chromatography ; Crystallin ; Data processing ; Desmin ; Detergents ; imaging ; Immunofluorescence ; Immunoprecipitation ; Intermediate filaments ; Light scattering ; Missense mutation ; Molecular modelling ; Muscular strength ; Myopathy ; Precipitation ; Skeletal muscle ; Vimentin
  • É parte de: PloS one, 2011-03, Vol.6 (3)
  • Notas: ObjectType-Article-2
    SourceType-Scholarly Journals-1
    content type line 23
    ObjectType-Feature-1
  • Descrição: An autosomal dominant missense mutation in I-B-crystallin (I-B-R120G) causes cataracts and desmin-related myopathy, but the underlying mechanisms are unknown. Here, we report the development of an I-B-R120G crystallin knock-in mouse model of these disorders. Knock-in I-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 I-B-crystallin, also increased in mutant lenses. In skeletal muscle, I-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 I-B-R120G knock-in mice share common mechanisms, including increased insolubility of I-B-crystallin and co-aggregation of I-B-crystallin with intermediate filament proteins. These knock-in I-B-R120G mice are a valuable model of the developmental and molecular biological mechanisms that underlie the pathophysiology of human hereditary cataracts and myopathy.
  • Idioma: Inglês
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  • Realização: ABCD-USP USP   Logos de Redes Sociais: Freepik

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