Abstract
Rett syndrome (RTT) is unique among genetic, chromosomal and other developmental disorders because of its extreme female gender bias, early normal development, and subsequent developmental regression with loss of motor and language skills. RTT is caused by heterozygosity for mutations in the X-linked gene MECP2, which encodes methyl-CpG binding protein 2. MeCP2 is a multifunctional protein that can act as an architectural chromatin-binding protein, a function that is unrelated to its ability to bind methyl-CpG and to attract chromatin modification complexes. Inactivating mutations that cause RTT in females are not prenatally lethal in males, but lead to profound congenital encephalopathy. Molecular diagnoses of RTT, through demonstration of a MECP2 mutation, made at an early stage of the disorder, usually confirm the sporadic nature and very low recurrence risk of the condition. A positive DNA test result, however, also predicts the inevitable clinical course, given the lack of effective intervention. Initial hypotheses indicating that the MeCP2 protein acts as a genome-wide transcriptional repressor were not confirmed by global gene expression studies in various tissues of individuals with RTT and mouse models of MeCP2 deficiency. Rather, recent evidence points to low-magnitude effects of a small number of genes—including the brain-derived neurotrophic factor pathway and glucocorticoid response genes—that might affect formation and maturation of synapses or synaptic function in postmitotic neurons.
Key Points
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Rett syndrome (RTT) in females is caused by heterozygous de novo mutations in the MECP2 (methyl-CpG binding protein 2) gene
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Null mutations in MECP2 that cause classic RTT in females are not prenatally lethal in boys, but cause a distinct form of congenital encephalopathy
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Functional genetic studies in mouse models of MeCP2 deficiency identified postmitotic neurons as the site for pathogenetic mechanisms, and highlighted the need for tight control of MeCP2 levels in the brain
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MeCP2 can act as an architectural chromatin binding protein, a function that is unrelated to its ability to bind methyl-CpG and attract chromatin modification complexes
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Although differential CpG methylation patterns are essential for epigenetic regulation of gene expression, there is no confirmed evidence that loss of MeCP2 function leads to epigenetic dysregulation in vivo in any of the systems studied
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Brain-derived neurotrophic factor (BDNF), a direct MeCP2 target, is able to modulate onset and disease progression in Mecp2 mutant mice, indicating potential therapeutic opportunities
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Acknowledgements
The author thanks Hong-Hua Li, ChaRandle Jordan, Birgitt Schüle and Pavel Belichenko for helpful discussions, Rick Cuevas for assistance with the manuscript, and the March of Dimes Birth Defects Foundation and the International Rett Syndrome Association for financial support.
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Francke, U. Mechanisms of Disease: neurogenetics of MeCP2 deficiency. Nat Rev Neurol 2, 212–221 (2006). https://doi.org/10.1038/ncpneuro0148
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DOI: https://doi.org/10.1038/ncpneuro0148
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