MeCP2 dysfunction in Rett syndrome and related disorders

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Rett syndrome, a neurodevelopmental disorder caused by mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (MeCP2), is a leading cause of mental retardation with autistic features in females. MECP2 mutations have also been identified in individuals with a variety of clinical syndromes, including mild learning-disability in females, neonatal encephalopathy in males, and psychiatric disorders, autism and X-linked mental retardation in both males and females. Furthermore, MECP2 duplications have been shown to cause a progressive postnatal neurological disorder. MeCP2 is a transcriptional repressor that binds to methylated CpG dinucleotides flanked by AT-rich segments and recruits a co-repressor complex, thereby altering chromatin structure. Subtle gene expression changes have been identified in Rett patients and mouse models; however, MeCP2 dysfunction has also been shown to cause abnormalities of RNA splicing, suggesting a complex molecular pathogenesis. Discovering which genes are misregulated in the absence of functional MeCP2 and demonstrating their role in causing neuronal dysfunction and disease manifestations are challenging but important steps for understanding the pathogenesis of Rett syndrome and related disorders.

Introduction

Rett syndrome (Online Mendelian Inheritance in Man [OMIM] database, 312750) is a postnatal neurodevelopmental disorder characterized by loss of acquired motor and language skills, autistic features, and unusual stereotyped movements (see Glossary) [1]. First described as a clinical entity by the pediatrician Andreas Rett in 1966 [2], Rett syndrome is classified in the Diagnostic and Statistical Manual of Mental Disorders as a pervasive developmental disorder — a group of disorders also including classic autism and Asperger's syndrome — and is the only pervasive developmental disorder with a known genetic cause. Rett syndrome is caused by mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (MeCP2) [3]. It is estimated that one out of every 10 000–15 000 females develops Rett syndrome [4]; however, MECP2 mutations cause a variety of additional neurodevelopmental disorders in both females and males, and the overall prevalence of MECP2 mutations in the population remains unknown. This review highlights recent research developments in the study of Rett syndrome and related disorders.

Section snippets

Neurological manifestations of classic Rett syndrome

Girls with Rett syndrome are born after an uneventful pregnancy and delivery. They are normal at birth and achieve expected developmental milestones until 6 to 18 months of age, when they develop deceleration of head growth, leading to microcephaly. They enter a period of regression characterized by loss of acquired language, cognitive, social and motor skills [1]. Cognitive impairments are a common feature of humans with MECP2 mutations. Language dysfunction and social withdrawal are also

MECP2 mutations in Rett syndrome and related disorders

MECP2 mutations account for up to 96% of classic Rett syndrome cases. The initial genetic studies showed that 70–75% of Rett syndrome cases had mutations in MECP2 [7]. The spectrum of MECP2 mutations causing Rett syndrome includes missense, frameshift and nonsense mutations, and intragenic deletions. Nearly 70% of the mutations arise from C–T transitions at eight CpG dinucleotides, whereas carboxy-terminal deletions are estimated to occur in 10–15% of patients. The MECP2 gene, located in Xq28

Methyl-CpG-binding protein 2

Current data support a model in which MeCP2 functions as a DNA methylation-dependent transcriptional repressor. MeCP2 was initially identified in a southwestern assay as an 80 kDa protein able to bind to DNA oligonucleotides containing at least one symmetrically methylated CpG dinucleotide [16]. The protein was shown to contain a methyl-CpG-binding domain required for binding to methylated DNA in vitro and for localization to highly methylated pericentromeric heterochromatin in cells in culture [

Mouse models of Rett syndrome

Three mouse models of Rett syndrome have been generated, each with different mutation type and phenotype severity. Using Cre-lox technology (see Glossary), Chen et al. [30] and Guy et al. [31] generated mice with fully deleted Mecp2 sequences (i.e. Mecp2 knockout mice). Mutant mice showed a period of apparently normal development followed by severe progressive neurological dysfunction leading to death at 7–10 weeks. Mutation of Mecp2 restricted to neuronal lineages resulted in a phenotype

Target genes of MeCP2

Although biochemical evidence suggested that MeCP2 functions as a global repressor of gene expression, transcriptional profiling failed to identify profound changes of gene expression in the brain of Mecp2 knockout mice [44]. Surprisingly, in these mice, minor changes in gene expression were found that became significant only when groups of genes were analyzed together [44]. Subsequent studies using a variety of approaches identified several putative target genes of MeCP2 in rodents and/or

Conclusions

The identification of the genetic cause of Rett syndrome, a predominantly sporadic disease, was a major advance in clinical neurology and genetics. In addition to enabling precise molecular diagnosis and genetic counseling, this discovery underscored the value of focusing on a handful of families to find genes for apparently sporadic disorders with complex neurological and behavioral phenotypes. Several areas of Rett syndrome research hold great promise for the next few years. Current data

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

The authors wish to thank members of the Zoghbi laboratory for feedback. We are grateful to Jeff Neul, Aaron Bowman and Bryan McGill for their critical reading of the manuscript. PM is supported by National Institutes of Health (NIH) NS049181, and March of Dimes Basil O’Connor Starter Scholar Research Award; HYZ is supported by NIH HD40301, funds from Cure Autism Now, and NIH HD24064 to the Baylor College of Medicine Mental Retardation and Developmental Disabilities Research Center. HYZ is an

Glossary

Cre-lox technology
A technology that enables selective deletion of sequences in vivo. The Cre recombinase recognizes specific DNA sequences known as LoxP sites and mediates recombination between them, which, in turn, will result in the excision of sequences flanked by the two LoxP sites.
Reporter minigene
An artificial DNA construct containing only a selected portion of a gene and designed to test aspects of gene regulation in cells in vitro.
Stereotyped movements
Repetitive, non-purposeful and

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