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.
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References
1.
Akbarian S, Chen RZ, Gribnau J, Rasmussen TP, Fong H, Jaenisch R, and others. 2001. Expression pattern of the Rett syndrome gene MeCP2 in primate prefrontal cortex . Neurobiol Dis8: 784–91 .
2.
Akhmanova A, Verkerk T, Langeveld A, Grosveld F, Galjart N. 2000. Characterisation of transcriptionally active and inactive chromatin domains in neurons . J Cell Sci113: 4463–74 .
3.
Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY. 1999. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2 . Nature Genet23: 185–8 .
Armstrong DD, Dunn JK, Antalffy B, Trivedi R. 1995. Selective dendritic alterations in the cortex of Rett syndrome . J Neuropath Exp Neurol54: 195–201 .
6.
Armstrong DD, Dunn JK, Schultz RJ, Herbert DA, Glaze DG, Motile KJ.1999. Organ growth in Rett syndrome, a post mortem examination analysis . Pediatr Neurol20: 125–9 .
7.
Balmer D, Arredondo J, Samaco RC, LaSalle JM. 2002. MECP2 mutations in Rett syndrome adversely affect lymphocyte growth, but do not affect imprinted gene expression in blood or brain . Hum Genet110: 545–52 .
8.
Bauman ML, Kemper TK, Arin DM. 1995. Pervasive neuroanatomic abnormalities of the brain in three cases of Rett syndrome . Neurology45: 1581–6 .
9.
Berman KF, Torrey EF, Daniel DG, Weinberger DR. 1992. Regional cerebral blood flow in monozygotic twins discordant and concordant for schizophrenia . Arch Gen Psychiatry49: 927–34 .
10.
Bird A. Guy J, Selfridge J, Barr H, Hendrich H., Kriaucionis S, and others. 2002. Functional studies of Mecp2-null mice . RSRF 3rd Ann Rett Syndrome Symposium, Baltimore, MD. p 12 .
Chen RZ, Akbarian S, Tudor M, Jaenisch R. 2001. Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rettlike phenotype in mice . Nat Genet27: 327–31 .
16.
Colantuoni C, Jeon OH, Hyder K, Chenchik A, Khimani AH, Narayanan V, and others. 2001. Gene expression profiling in postmortem Rett Syndrome brain: differential gene expression and patient classification . Neurobiol Dis8: 847–65 .
17.
Coy JF, Sedlacek Z, Bachner D, Delius H, Poustka A. 1999. A complex pattern of evolutionary conservation and alternative polyadenylation within the long 3”-untranslated region of the methyl-CpG-binding protein 2 gene (MeCP2) suggests a regulatory role in gene expression . Hum Mol Genet8: 1253–62 .
18.
Francke U. 2002. Understanding Rett Syndrome—Where are we? RSRF 3rd Ann Rett Syndrome Symposium, Baltimore, MD. p 1 .
19.
Franzen G, Ingvar DH. 1975. Abnormal distribution of cerebral activity in chronic schizophrenia . J Psychiatr Res12: 199–214 .
20.
Guy J, Hendrich B, Holmes M, Martin JE, Bird A. 2001. A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome . Nat Genet27: 322–6 .
21.
Hagberg, B. 1985. Rett’s syndrome: prevalence and impact on progressive severe mental retardation in girls . Acta Paediatr Scand74: 405–8 .
22.
Hansen JC, Georgel P, Wade H. 2002. In vitro interactions of native and mutant MeCP2 with DNA and chromatin . RSRF 3rd Ann Rett Syndrome Symposium, Baltimore, MD. p 24 .
23.
Henikoff S, Ahmad K, Malik HS. 2001. The centromere paradox: stable inheritance with rapidly evolving DNA . Science293: 1098–102 .
24.
Huppke P, Held M, Hanefeld F, Engel W, Laccone F. 2002. Influence of mutation type and location on phenotype in 123 patients with rett syndrome . Neuropediatrics33: 63–8 .
25.
Jaenisch R, Luikenhuis S, Tudor M, Beard C, Chang Q. 2002. Molecular analysis of Mecp2 deficiency in mice . RSRF 3rd Ann Rett Syndrome Symposium, Baltimore, MD. p 10 .
26.
Jellinger K, Armstrong D, Zoghbi HY, Percy AK. 1988. Neuropathology of Rett syndrome . Acta Neuropathol76: 142–58 .
27.
Jones PL, Veenstra GJ, Wade PA, Vermaak D, Kass SU, Landsberger N, and others. 1998. Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription . Nat Genet19: 187–91 .
28.
Kaludov NK, Wolffe AP. 2000. MeCP2 driven transcriptional repression in vitro: selectivity for methylated DNA, action at a distance and contacts with the basal transcription machinery . Nucleic Acids Res28: 1921–8 .
29.
Kaufmann WE. 2002. MeCP2 expression in human neocortex . RSRF 3rd Annual Rett Syndrome Symposium, Baltimore, MD. p 21 .
30.
Kerr AM, Nomura Y, Armstrong D, Anvret M, Belichenko PV, Budden S, and others. 2001. Guidelines for reporting clinical features in cases with MECP2 mutations . Brain Dev23: 208–11 .
31.
Kudo S. 1998. Methyl-CpG-binding protein MeCP2 represses Sp1-activated transcription of the human leukosialin gene when the promoter is methylated . Mol Cell Biol18: 5492–9 .
32.
Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J, and others. 2001. Initial sequencing and analysis of the human genome . Nature409: 860–921 .
33.
Lewis JD, Meehan RR, Wenzel WJ, Maurer-Fogy I, Jeppesen P, Klein F, and others. 1992. Purification, sequence, and cellular localization of a novel chromosomal protein that binds to methylated DNA . Cell69: 905–14 .
34.
Liang F, Jones EG. 1997. Differential and time-dependent changes in gene expression for type II calcium/calmodulin-dependent protein kinase, 67 kDa glutamic acid decarboxylase, and glutamate receptor subunits in tetanus toxin-induced focal epilepsy . J Neurosci17: 2168–80 .
35.
Marin-Padilla M. 1988. Early ontogenesis of the human cerebral cortex. In: Peters A, Jones EG, editors. Cerebral cortex, Vol. 7. New York: Plenum . p 1–30.
36.
Mirnics K, Middleton FA, Marquez A, Lewis DA, Levitt P. 2000. Molecular characterization of schizophrenia viewed by microarray analysis of gene expression in prefrontal cortex . Neuron28: 53–67 .
37.
Naidu S. 1997. Rett syndrome: a disorder affecting early brain growth . Ann Neurol42: 3–10 .
38.
Nan X, Campoy FJ, Bird A. 1997. MeCP2 is a transcriptional repressor with abundant binding sites in genomic chromatin . Cell88: 471–81 .
39.
Nan X, Meehan RR, Bird A. 1993. Dissection of the methyl-CpG binding domain from the chromosomal protein MeCP2 . Nucleic Acids Res21: 4886–92 .
40.
Nan X, Ng HH, Johnson CA, Laherty CD, Turner BM, Eisenman RN, and others. 1998. Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex . Nature393: 386–9 .
41.
Nielsen JB, Friberg L, Lou H, Lassen NA, Sam IL. 1990. Immature pattern of brain activity in Rett syndrome . Arch Neurol47: 982–6 .
42.
Partridge JF, Borgstrom B, Allshire RC. 2000. Distinct protein interaction domains and protein spreading in a complex centromere . Genes Dev14: 783–91 .
43.
Percy AK. 2001. Rett syndrome: clinical correlates of the newly discovered gene . Brain Dev23(Suppl 1): S202–5 .
44.
Rakic P. 1974. Neurons in rhesus monkey visual cortex: systematic relationship between time of origin and eventual disposition . Science183: 425–7 .
45.
Rett A. 1966. On a unusual brain atrophy syndrome in hyperammonemia in childhood . Wien Med Wochenschr116: 723–6 .
46.
Schanen C. 2001. Rethinking the fate of males with mutations in the gene that causes Rett syndrome . Brain Dev23(Suppl 1): S144–6 .
47.
Schultz RJ, Glaze DG, Motil KJ, Armstrong DD, del Junco DJ, Hubbard CR, and others. 1993. The pattern of growth failure in Rett syndrome . Am J Dis Child147: 633–7 .
48.
Shahbazian MD, Antalffy B, Armstrong DL, Zoghbi HY. 2002. Insight into Rett syndrome: MeCP2 levels display tissue- and cell-specific differences and correlate with neuronal maturation . Hum Mol Genet11: 115–24 .
49.
Subramaniam B, Naidu S, Reiss AL. 1997. Neuroanatomy in Rett Syndrome: cerebral cortex and posterior fossa . Neurology48: 399–407 .
50.
Taddei A, Maison C, Roche D, Almouzni G. 2001. Reversible disruption of pericentric heterochromatin and centromere function by inhibiting deacetylases . Nat Cell Biol3: 114–20 .
51.
Tudor M, Akbarian S, Chen RZ, Jaenisch R. 2002. Transcriptional profiling of a mouse model for Rett syndrome reveals subtle transcriptional changes in brain . Proc Natl Acad Sci USA99: 15536–41 .
52.
Van den Veyver IB, Zoghbi HY. 2001. Mutations in the gene encoding methyl-CpG-binding protein 2 cause Rett syndrome . Brain Dev23(Suppl 1): S147–51 .
53.
Watson P, Black G, Ramsden S, Barrow M, Super M, Kerr B, and others. 2001. Angelman syndrome phenotype associated with mutations in MECP2, a gene encoding a methyl CpG binding protein . J Med Genet38: 224–8 .
54.
Weitzel JM, Buhrmester H, Stratling WH. 1997. Chicken MAR-binding protein ARBP is homologous to rat methyl-CpG-binding protein MeCP2 . Mol Cell Biol17: 5656–66 .
55.
Yu F, Zingler N, Schumann G, Stratling WH. 2001. Methyl-CpG-binding protein 2 represses LINE-1 expression and retrotransposition but not Alu transcription . Nucleic Acids Res29: 4493–501 .
