Rett Syndrome

Margaret K Bradbury, Research Center for Genetic Medicine, Children's National Medical Center, Washington, DC, USA
Kristen C Hoffbuhr, Research Center for Genetic Medicine, Children's National Medical Center, Washington, DC, USA
Eric P Hoffman, Research Center for Genetic Medicine, Children's National Medical Center, Washington, DC, USA

Published online: September 2007

DOI: 10.1002/9780470015902.a0005687.pub2

Rett syndrome is a neurological disease of early postnatal brain growth found almost exclusively in girls and is the third most common cause, after Down syndrome and Fragile X syndrome, of severe mental retardation. Typically, girls with Rett syndrome show developmental regression including loss of communication and motor skills, stereotypic hand movements and a deceleration of head growth. The defective gene, methyl CpG binding protein 2 (Rett syndrome) (MECP2) is normally involved in the transcription silencing of genes (turning genes ‘off ’). In Rett syndrome, the MECP2 protein does not work properly in approximately half of the patient's cells due to X inactivation. This is thought to lead to inappropriate communication between MECP2-positive and MECP2-negative cells in the brain, and the Rett syndrome phenotype.

Keywords: Rett syndrome; RTT; neurological disorder; MECP2; X-inactivation; CDKL2

Figure 1. Role of MECP2 in transcription silencing and Rett syndrome. Representative diagram of MECP2-mediated silencing of genes (top panel). MECP2 binds methylcytosines (CmG) and recruits transcriptional repressor Sin3a and histone deacetylase HDAC1 and HDAC2 to the MECP2–DNA complex. HDAC1 and HDAC2 remove acetyl moieties from histones. Deacetylated histones, which are more negatively charged, cause the chromatin to become more compacted, leading to the silencing of genes. As shown by the lower diagram, MECP2 does not function properly in Rett syndrome, leading to the expression of genes normally regulated by MECP2.
Figure 2. Schematic diagrams of the MECP2 gene and common mutations in Rett syndrome. The MECP2 gene consists of four exons (E1–E4), three introns and a large (>8.5 kb) 3¢ untranslated region (3¢-UTR). The two highly conserved regions of the gene are the methyl-binding domain (MBD) and the transcriptional repression domain (TRD).
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 Further Reading
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    Deng V, Matagne V, Banine F et al. (2007) FXYD1 is a MeCP2 target gene overexpressed in the brains of Rett syndrome patients and Mecp2-null mice. Human Molecular Genetics 15;16(6): 640–650.
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    Hogart A, Nagarajan RP, Patzel KA, Yasui DH and Lasalle JM (2007) 15q11-13 GABAA receptor genes are normally biallelically expressed in brain yet are subject to epigenetic dysregulation in autism-spectrum disorders. Human Molecular Genetics 15;16(6): 691–703.
    book Hunter K (1999) The Rett Syndrome Handbook. Clinton, MD: International Rett Syndrome Association.
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    Van Esch H, Jansen A, Bauters M, Froyen G and Fryns JP (2007) Encephalopathy and bilateral cataract in a boy with an interstitial deletion of Xp22 comprising the CDKL5 and NHS genes. American Journal of Medical Genetics A. 15 143(4): 364–369.
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 Web Links
    ePath GeneReviews: www.Genetests.org, enter in Rett syndrome
    ePath Methyl CpG binding protein 2 (Rett syndrome) (MECP2); Locus ID: 4204. LocusLink: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene&cmd=Retrieve&dopt=full_report&list_uids=4204
    ePath Methyl CpG binding protein 2 (Rett syndrome) (MECP2); MIM number: 312750. OMIM: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=312750

Related Sub-Topics:

Neurobiology of Disease | Organisation of the Nervous System | Nervous System Development | Genes, Molecules and Cellular Processes | Development of Vertebrate Nervous System | Developmental Disorders | Organogenesis | Genetics of Intelligence and Cognition | Specific Genetic Disorders | Chromosomal Disorders | Epigenetics and Disease | Genetic Counseling
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Article Title: Rett Syndrome
 
How to Cite close
Bradbury, Margaret K, Hoffbuhr, Kristen C, and Hoffman, Eric P(Sep 2007) Rett Syndrome. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0005687.pub2]