Rett syndrome: disruption of epigenetic control of postnatal neurological functions

• Published in: Human molecular genetics Vol. 24; no. R1; pp. R10 - R16
• Main Authors: Pohodich, Amy E, Zoghbi, Huda Y
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 15.10.2015
• Subjects: Brain - cytology; Brain - growth & development; Brain - metabolism; Chromatin - metabolism; Epigenesis, Genetic; Female; Humans; Invited Reviews; Male; Methyl-CpG-Binding Protein 2 - genetics; Methyl-CpG-Binding Protein 2 - metabolism; Neurodevelopmental Disorders - genetics; Neurodevelopmental Disorders - metabolism; Neurons - metabolism; Rett Syndrome - genetics; Rett Syndrome - metabolism; Transcription, Genetic
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddv217

Loss-of-function mutations in the X-linked gene Methyl-CpG-binding protein 2 (MECP2) cause a devastating pediatric neurological disorder called Rett syndrome. In males, these mutations typically result in severe neonatal encephalopathy and early lethality. On the other hand, owing to expression of the normal allele in ∼50% of cells, females do not suffer encephalopathy but instead develop Rett syndrome. Typically females with Rett syndrome exhibit a delayed onset of neurologic dysfunction that manifests around the child's first birthday and progresses over the next few years. Features of this disorder include loss of acquired language and motor skills, intellectual impairment and hand stereotypies. The developmental regression observed in patients with Rett syndrome arises from altered neuronal function and is not the result of neurodegeneration. Maintenance of an appropriate level of MeCP2 appears integral to the function of healthy neurons as patients with increased levels of MeCP2, owing to duplication of the Xq28 region encompassing the MECP2 locus, also present with intellectual disability and progressive neurologic symptoms. Despite major efforts over the past two decades to elucidate the molecular functions of MeCP2, the mechanisms underlying the delayed appearance of symptoms remain unclear. In this review, we will highlight recent findings that have expanded our knowledge of MeCP2's functions, and we will discuss how epigenetic regulation, chromatin organization and circuit dynamics may contribute to the postnatal onset of Rett syndrome.