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Articles by D. M Robins
Total Records ( 1 ) for D. M Robins
  Z Yu , A. M Wang , D. M Robins and A. P. Lieberman
  Zhigang Yu, Adrienne M. Wang, Diane M. Robins, and Andrew P. Lieberman

Here, we used a mouse model of Kennedy disease, a degenerative disorder caused by an expanded CAG repeat in the androgen receptor (AR) gene, to explore pathways leading to cellular dysfunction. We demonstrate that male mice containing a targeted Ar allele with 113 CAG repeats (AR113Q mice) exhibit hormone- and glutamine length-dependent missplicing of Clcn1 RNA in skeletal muscle. Changes in RNA splicing are associated with increased expression of the RNA-binding protein CUGBP1. Furthermore, we show that skeletal muscle denervation in the absence of a repeat expansion leads to increased CUGBP1 expression. However, this induction of CUGBP1 is not sufficient to alter Clcn1 RNA splicing, indicating that changes mediated by both denervation and AR113Q toxicity contribute to altered RNA processing. To test this notion directly, we exogenously expressed the AR in vitro and observed hormone-dependent changes in the splicing of pre-mRNAs from a human cardiac troponin T minigene. These effects were notably similar to changes mediated by RNA with expanded CUG tracts, but not CAG tracts, highlighting unanticipated similarities between CAG and CUG repeat diseases. The expanded glutamine AR also altered hormone-dependent splicing of a calcitonin/calcitonin gene-related peptide minigene, suggesting that toxicity of the mutant protein additionally affects RNA processing pathways that are distinct from those regulated by CUGBP1. Our studies demonstrate the occurrence of hormone-dependent alterations in RNA splicing in Kennedy disease models, and they indicate that these changes are mediated by both the cell-autonomous effects of the expanded glutamine AR protein and by alterations in skeletal muscle that are secondary to denervation.

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