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  • Review Article
  • Published:

Molecular genetics of Rett syndrome: when DNA methylation goes unrecognized

Nature Reviews Genetics volume 7, pages 415–426 (2006)Cite this article

A Corrigendum to this article was published on 01 July 2006

Key Points

  • Rett syndrome is an X-linked dominant neurodevelopmental disorder that affects patients many months after birth, following a period of apparently normal growth and development. It occurs almost exclusively in females, at an incidence of 1/10,000 to 1/15,000 live births.

  • The genetic defects that are responsible for Rett syndrome affect the gene MECP2, which encodes methyl-CpG binding protein 2. Females with Rett syndrome are heterozygous for a de novo mutation in MECP2.

  • Mutations in MECP2, including duplications of the whole gene, are also present at a low frequency in males, and are associated with a range of phenotypes that extend from severe encephalopathy to mild mental retardation.

  • Rett-like syndromes can result from mutations in CDKL5 (cyclin-dependent kinase-like 5), which encodes a serine/threonine kinase that interacts with MeCP2.

  • MeCP2 expression is highly regulated in neurons, and its level increases progressively with neuronal differentiation and maturation.

  • MeCP2 binds methylated DNA and functions as a transcriptional-repressor regulator through a complex that includes the co-repressor SIN3A and histone deacetylases.

  • Knock-out and knock-in Mecp2 mice models, as well as conditional inactivation in mice of MeCP2 in post-mitotic neuronal cells and in postnatal stages, recapitulate symptoms of human Rett syndrome phenotypes.

  • Most transcriptomic studies that have used either animal models or cell lines from patients with Rett syndrome have failed to identify genes that are regulated by MeCP2. However, candidate-gene-based expression studies have contributed into the identification of genes such as BDNF (brain-derived neurotrophic factor), DLX5 (distal-less homeobox 5), UBE3A (ubiquitin protein ligase E3A) and GABRB3 (γ-aminobutyric-acid receptor 3) that are differentially expressed in these systems.

  • The expression of BDNF, a factor that is involved in neuronal morphogenesis and maturation, is deregulated in MeCP2-deficient mice. Intriguingly, BDNF expression is increased at the mRNA level and decreased at the protein level in these mice.

  • In addition to its chromatin-remodelling and transcriptional-regulatory functions, MeCP2 also regulates the expression of genes that are located in imprinted genomic regions and is thought to function as a splicing regulator of neuronal transcripts.

  • MeCP2 does not seem to be a global gene repressor; the evidence that is emerging indicates that Rett syndrome might result from the altered expression of a few key genes that are involved in postnatal, experience-dependent neuronal activity.

Abstract

The discovery that Rett syndrome is caused by mutations that affect the methyl-CpG-binding protein MeCP2 provided a major breakthrough in understanding this severe neurodevelopmental disorder. Animal models and expression studies have contributed to defining the role of MeCP2 in development, highlighting its contribution to postnatal neuronal morphogenesis and function. Furthermore, in vitro assays and microrray studies have delineated the potential molecular mechanisms of MeCP2 function, and have indicated a role in the transcriptional silencing of specific target genes. As well as unravelling the mechanisms that underlie Rett syndrome, these studies provide more general insights into how DNA-methylation patterns are recognized and translated into biological outcomes.

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Figure 1: The MECP2 gene and its protein products.
Figure 2: Mutations in CDKL5 that are found in patients with atypical Rett syndrome.
Figure 3: MeCP2 regulation of chromatin remodelling and transcription.
Figure 4: Regulation of imprinted regions by MeCP2.
Figure 5: Regulation of alternative splicing by MeCP2.

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Acknowledgements

We apologize to those whose work could not be cited owing to space limitations. We are grateful to the French Association for Rett Syndrome (AFSR). We would like to thank F. Francis for helpful comments. Work in the authors' laboratory is supported by research grants from the European Commission, GIS-Maladies Rares and Fondation France Telecom.

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Authors and Affiliations

  1. Institut Cochin, Départment de Génétique et Developpement, Paris, F-75014, France

    Thierry Bienvenu & Jamel Chelly

  2. Inserm, U567, Paris, F-75014, France

    Thierry Bienvenu & Jamel Chelly

  3. Université Paris René Descartes, UMR-S8104, Paris, F-75014, France

    Thierry Bienvenu & Jamel Chelly

  4. Laboratoire de Biochimie et Génétique Moléculaires, Assistance-Publique-Hôpitaux de Paris, Hôpital Cochin, Paris, F-75014, France

    Thierry Bienvenu & Jamel Chelly

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Correspondence to Jamel Chelly.

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Glossary

Encephalopathy

A degenerative condition of the brain that can be caused by infectious disease, metabolic abnormalities, brain tumours, toxic drug effects or increased intercranial pressure.

Array CGH

A technique that uses comparative genomic hybridization on microarrays to determine copy-number differences between DNA sequences.

Nestin

A class VI intermediate-filament protein that is expressed during early embryonic development in mammals but is absent from nearly all mature CNS cells.

Basal ganglia

Clusters of neurons that are located deep in the brain that relay messages between the most anterior part of the cortex that is involved in problem solving and complex thought, and the lower motor and sensory areas; includes the striatum.

Kyphosis

Abnormal curvature of the thoracic spine.

Astrocyte

A star-shaped neuroglial cell that surrounds and supports neurons in the CNS.

Oligodendrocyte

A type of non-neuronal cell that lacks axons and dendrites and insulates axons so that they can send electric impulses. These are also myelin-producing cells.

Dendritic arborization

The process that leads to the production of the numerous dendrites that characterize many neurons, and the branches that project from these dendrites.

Dendritic spine

Mushroom-shaped structures on neuronal dendrites that receive synaptic input and are the sites of postsynaptic densities. Changes in spine shape are thought to be important for modulating synaptic strength.

Morpholinos

Oligonucleotides that are efficient gene-silencing reagents, and that can either block translation initiation in the cytosol or modify pre-mRNA splicing in the nucleus (by targeting splice junctions).

PC12 cells

A clonal cell line that responds reversibly to nerve growth factor.

Prader-Willi syndrome

A genetic disorder that is caused by loss of paternally expressed genes that are located in the 4-Mb imprinted region of 15q11–q13. Features of the disorder include excessive eating (hyperphagia), obesity, short stature, mental retardation or learning disabilities, and behavioural problems.

Angelman syndrome

A genetic disorder that is caused by several genetic mechanisms that inactivate or disrupt the maternally derived UBE3A. Symptoms include hyperactivity, ataxia, problems with speech and language, and an unusually happy demeanour.

Ubiquitin ligase

A protein that is involved in polyubiquitylation that covalently attaches ubiquitin to a lysine residue on a target protein. Polyubiquitylation marks proteins for degradation by the proteasome.

γ-Aminobutyric acid

A major inhibitory neurotransmitter in the mammalian CNS that participates in the regulation of neuronal excitability through interaction with specific receptors.

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Bienvenu, T., Chelly, J. Molecular genetics of Rett syndrome: when DNA methylation goes unrecognized. Nat Rev Genet 7, 415–426 (2006). https://doi.org/10.1038/nrg1878

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