Young, Juan I., Hong, Eugene P., Castle, John C., Crespo-Barreto, Juan, Bowman, Aaron B., Rose, Matthew F., Dongcheul Kang, Richman, Ron, Johnson, Jason M., Bergett, Susan, and Zoghbi, Huda V.
Rett syndrome (RTT) is a postnatal neurodevelopmental disorder characterized by the loss of acquired motor and language skills, autistic features, and unusual stereotyped movements. RTT is caused by mutations in the X-linked gene encoding methyl-CpG binding protein 2 (MeCP2). Mutations in MECP2 cause a variety of neurodevelopmental disorders including X-linked mental retardation, psychiatric disorders, and some cases of autism. Although MeCP2 was identified as a methylation-dependent transcriptional repressor, transcriptional profiling of RNAs from mice lacking MeCP2 did not reveal significant gene expression changes, suggesting that MeCP2 does not simply function as a global repressor. Changes in expression of a few genes have been observed, but these alterations do not explain the full spectrum of Rett-like phenotypes, raising the possibility that additional MeCP2 functions play a role in pathogenesis. In this study, we show that MeCP2 interacts with the RNA-binding protein V box-binding protein I and regulates splicing of reporter minigenes. Importantly, we found aberrant alternative splicing patterns in a mouse model of RU. Thus, we uncovered a previously uncharacterized function of MeCP2 that involves regulation of splicing, in addition to its role as a transcriptional repressor. [ABSTRACT FROM AUTHOR]