Expanded glutamine repeats trigger protein misfolding and contribute to a variety of neurodegenerative diseases through unknown mechanisms. In Kennedy disease, the repeat expansion occurs in the androgen receptor and results in a hormone-dependent loss of motor neurons, causing cramps and muscle weakness. Here, Zhigang Yu and colleagues report that the mutant protein produced in Kennedy disease alters RNA splicing by a mechanism that requires male hormones and correlates with the length of the glutamine repeat. Since pathological changes in RNA splicing are recognized in related diseases, other mutant proteins that are formed from extended repeats may produce similar RNA processing changes that contribute to cellular dysfunction.

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