{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T22:11:31Z","timestamp":1784758291804,"version":"3.55.0"},"reference-count":81,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T00:00:00Z","timestamp":1778457600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurol."],"abstract":"<jats:p>Rett Syndrome (RTT), a severe neurodevelopmental disorder, is caused by mutations in the X-linked MECP2 gene, which encodes a key chromatin-modifying protein. Originally described as a transcriptional repressor due to its ability to bind methylated DNA, RTT pathology was first to the misregulation of target genes. However, we present a synthesis of recent research that could re-frame the etiology of the disease. This model proposes that MECP2 deficiency triggers a cellular stress response that is one of the direct and primary causes of RTT pathology. The central hypothesis emerging from this body of work is that the loss of MECP2 function directly impairs cellular machinery for DNA repair. This failure in genomic maintenance results in an accumulation of DNA damage, which acts as a primary trigger for a senescence response triggered by the p53 pathway. This senescent state initiates a cascade of downstream physiological deficits, including severe metabolic dysfunction, reduced dendritic branching, and impaired synaptic activity. This model represents a repositioning of RTT from a disorder of simple transcriptional misregulation to a complex pathology rooted in a fundamental failure of genomic integrity and cellular homeostasis. The findings open new, targeted therapeutic avenues and offer not only a potential mechanistic understanding of RTT, and potentially other Intellectual Disability syndromes caused by mutations in genes that act in the same pathways.<\/jats:p>","DOI":"10.3389\/fneur.2026.1711771","type":"journal-article","created":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T04:27:25Z","timestamp":1778473645000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["New insights into Rett syndrome pathogenesis: defining the role of MEPC2 in DNA damage"],"prefix":"10.3389","volume":"17","author":[{"given":"Niloufar","family":"Mansooralavi","sequence":"first","affiliation":[{"name":"Molecular Biology Institute, IDDRC, UCLA","place":["Los Angeles, CA, United States"]},{"name":"Department of Molecular Cell and Developmental Biology, IDDRC, UCLA","place":["Los Angeles, CA, United States"]},{"name":"Broad Center for Regenerative Medicine, IDDRC, UCLA, Los Angeles, CA, Jonsson Comprehensive Cancer Center, IDDRC, UCLA","place":["Los Angeles, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William E.","family":"Lowry","sequence":"additional","affiliation":[{"name":"Molecular Biology Institute, IDDRC, UCLA","place":["Los Angeles, CA, United States"]},{"name":"Department of Molecular Cell and Developmental Biology, IDDRC, UCLA","place":["Los Angeles, CA, United States"]},{"name":"Broad Center for Regenerative Medicine, IDDRC, UCLA, Los Angeles, CA, Jonsson Comprehensive Cancer Center, IDDRC, UCLA","place":["Los Angeles, CA, United States"]},{"name":"Division of Dermatology, DGSOM, IDDRC, UCLA","place":["Los Angeles, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,11]]},"reference":[{"key":"ref1","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1016\/0092-8674(92)90610-O","article-title":"Purification, sequence, and cellular localization of a novel chromosomal protein that binds to methylated DNA","volume":"69","author":"Lewis","year":"1992","journal-title":"Cell"},{"key":"ref2","doi-asserted-by":"crossref","first-page":"5085","DOI":"10.1093\/nar\/20.19.5085","article-title":"Characterization of MeCP2, a vertebrate DNA binding protein with affinity for methylated DNA","volume":"20","author":"Meehan","year":"1992","journal-title":"Nucleic Acids Res"},{"key":"ref3","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1016\/S0092-8674(00)81887-5","article-title":"MeCP2 is a transcriptional repressor with abundant binding sites in genomic chromatin","volume":"88","author":"Nan","year":"1997","journal-title":"Cell"},{"key":"ref4","doi-asserted-by":"crossref","first-page":"1943","DOI":"10.1016\/j.neuron.2024.04.007","article-title":"MECP2 directly interacts with RNA polymerase II to modulate transcription in human neurons","volume":"112","author":"Liu","year":"2024","journal-title":"Neuron"},{"key":"ref5","first-page":"6","article-title":"Gene silencing by methyl-CpG-binding proteins","volume":"214","author":"Nan","year":"1998","journal-title":"Novartis Found Symp"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"386","DOI":"10.1038\/30764","article-title":"Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex","volume":"393","author":"Nan","year":"1998","journal-title":"Nature"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"784","DOI":"10.1006\/nbdi.2001.0420","article-title":"Expression pattern of the Rett syndrome gene MeCP2 in primate prefrontal cortex","volume":"8","author":"Akbarian","year":"2001","journal-title":"Neurobiol Dis"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"6033","DOI":"10.1073\/pnas.0401626101","article-title":"Expression of MeCP2 in postmitotic neurons rescues Rett syndrome in mice","volume":"101","author":"Luikenhuis","year":"2004","journal-title":"Proc Natl Acad Sci USA"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1038\/85906","article-title":"Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice","volume":"27","author":"Chen","year":"2001","journal-title":"Nat Genet"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"322","DOI":"10.1038\/85899","article-title":"A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome","volume":"27","author":"Guy","year":"2001","journal-title":"Nat Genet"},{"key":"ref11","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1055\/s-2007-979734","article-title":"Oxidative metabolism in Rett syndrome: 1. 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