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

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 * Rett syndrome (RTT) in females is caused by heterozygous _de novo_ mutations in the _MECP2_ (methyl-CpG binding protein 2)

gene * Null mutations in _MECP2_ that cause classic RTT in females are not prenatally lethal in boys, but cause a distinct form of congenital encephalopathy * 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 * 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 * 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 * Brain-derived neurotrophic factor (BDNF), a direct MeCP2 target, is able to modulate onset and disease progression in _Mecp2_ mutant mice, indicating potential

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our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS EXPLORING THE COMPLEXITY OF MECP2 FUNCTION IN RETT SYNDROME Article 13 May 2025 RETT SYNDROME Article 07 November

2024 MYT1L IN THE MAKING: EMERGING INSIGHTS ON FUNCTIONS OF A NEURODEVELOPMENTAL DISORDER GENE Article Open access 22 July 2022 REFERENCES * Rett A (1966) Uber ein eigenartiges

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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. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * a professor of genetics and pediatrics at Stanford University School of Medicine, Stanford, CA, USA

Uta Francke Authors * Uta Francke View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Uta Francke. ETHICS DECLARATIONS

COMPETING INTERESTS The author declares no competing financial interests. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Francke, U. Mechanisms of

Disease: neurogenetics of MeCP2 deficiency. _Nat Rev Neurol_ 2, 212–221 (2006). https://doi.org/10.1038/ncpneuro0148 Download citation * Received: 05 August 2005 * Accepted: 24 January 2006

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