The Neurobiology of Rett Syndrome

Abstract

Rett syndrome is a neuropsychiatric disorder with onset in early childhood. Loss-of-function mutations of the X-linked gene encoding methyl-CpG binding protein 2 ( MECP2) are responsible for more than 80% of Rett cases. Despite these recent advances in molecular genetics, little is known about the neurobiology of Rett syndrome and the role of MeCP2 protein in the nervous system. The molecular functions of the MeCP2 protein were primarily studied in nonneuronal cell lines and in vitro systems; MeCP2 binds primarily, but not exclusively, to methylated DNA, and it is thought to regulate gene expression, chromatin composition, and chromosomal architecture. In the brain, MeCP2 appears to be expressed ubiquitously by neurons. There is increasing evidence that the protein is important for maintenance of neuronal chromatin during late development and in adulthood. Levels of MeCP2 expression increase during the course of neuronal differentiation and remain at high levels in the adult brain. Furthermore, genetic studies in mice demonstrated that the selective deletion of the Mecp2 gene in neurons results several weeks later in a Rett-like phenotype, including a reduction in brain weight and neuronal dystrophy. Rett syndrome is not accompanied by a neurodegenerative process and thus perhaps may be amenable to therapeutic intervention at the time of symptom expression.