Curr Opin Genet Dev. 2006 Apr 27; [Epub ahead of print]
MeCP2 dysfunction in Rett syndrome and related disorders
Moretti P, Zoghbi HY.
Baylor College of Medicine, Houston, TX
Abstract
Rett syndrome, a neurodevelopmental disorder caused by mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (MeCP2), is a leading cause of mental retardation with autistic features in females. MECP2 mutations have also been identified in individuals with a variety of clinical syndromes, including mild learning-disability in females, neonatal encephalopathy in males, and psychiatric disorders, autism and X-linked mental retardation in both males and females. Furthermore, MECP2 duplications have been shown to cause a progressive postnatal neurological disorder. MeCP2 is a transcriptional repressor that binds to methylated CpG dinucleotides flanked by AT-rich segments and recruits a co-repressor complex, thereby altering chromatin structure. Subtle gene expression changes have been identified in Rett patients and mouse models; however, MeCP2 dysfunction has also been shown to cause abnormalities of RNA splicing, suggesting a complex molecular pathogenesis. Discovering which genes are misregulated in the absence of functional MeCP2 and demonstrating their role in causing neuronal dysfunction and disease manifestations are challenging but important steps for understanding the pathogenesis of Rett syndrome and related disorders.Lay Summary
In this review targeted to scientists familiar with Rett syndrome, the authors highlight recent research developments. Specifically, they focus on key papers of particular interest published within the last year, which discuss the role of MeCP2, mouse models of Rett syndrome, and target genes of MeCP2. They then propose several areas of Rett research which should hold great promise for the next few years. Overall, this important paper succinctly reviews the current state of research for those working in this ever-growing scientific discipline.