{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T12:42:57Z","timestamp":1785415377565,"version":"3.56.0"},"posted":{"date-parts":[[2025,9,3]]},"group-title":"Genetics","reference-count":63,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,9,3]],"date-time":"2025-09-03T00:00:00Z","timestamp":1756857600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"award":["222507\/Z\/21\/Z"],"award-info":[{"award-number":["222507\/Z\/21\/Z"]}],"id":[{"id":"https:\/\/ror.org\/029chgv08","id-type":"ROR","asserted-by":"publisher"}]},{"award":["13669477_13669480"],"award-info":[{"award-number":["13669477_13669480"]}],"id":[{"id":"https:\/\/ror.org\/03s455144","id-type":"ROR","asserted-by":"publisher"}]},{"award":["13800235_13800239"],"award-info":[{"award-number":["13800235_13800239"]}],"id":[{"id":"https:\/\/ror.org\/01gghaa40","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["DP2CA281401"],"award-info":[{"award-number":["DP2CA281401"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,22]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Mutations in the\n                  <jats:italic>MECP2<\/jats:italic>\n                  gene cause the severe neurological disorder Rett syndrome. A cluster of frameshift-causing C-terminal deletions (CTDs) lead to loss of \u223c100 amino acids at the C-terminus of the MeCP2 protein, and account for approximately 10% of RTT-causing mutations. The pathogenicity of C-terminal deletions (CTDs) is unexpected, as this C-terminal domain is non-essential in mice. Utilising databases of pathogenic and benign human\n                  <jats:italic>MECP2<\/jats:italic>\n                  mutations, we find that some individuals with apparently typical CTDs do not exhibit Rett syndrome, confirming that C-terminal truncations are not intrinsically pathogenic. Using human DNA sequence data and mouse models, we demonstrate that pathogenicity results from a drastic reduction in MeCP2 levels and is determined by the presence of the short amino acid motif proline-proline-stop (-PPX) at the C-terminus, which results from a shift to the +2 reading frame. Individuals with CTDs that shift to the +1 frame avoid this motif and do not develop Rett syndrome. Mutating the stop codon of the PPX motif to tryptophan rescues MeCP2 expression and RTT-like phenotypes in a CTD mouse model. Finally, we demonstrate that an adenine base editor can efficiently introduce this tryptophan substitution in cultured cells. Overall, our findings uncover a simple and reliable prognostic distinction between benign and pathogenic CTDs and provide proof-of-concept for an editing strategy that potentially corrects all disease-causing CTD mutations.\n                <\/jats:p>","DOI":"10.1101\/2025.08.31.673354","type":"posted-content","created":{"date-parts":[[2025,9,4]],"date-time":"2025-09-04T00:20:12Z","timestamp":1756945212000},"source":"Crossref","is-referenced-by-count":0,"title":["Translational reading frame determines the pathogenicity of C-terminal frameshift deletions in MeCP2: an alternative therapeutic approach"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8440-5667","authenticated-orcid":false,"given":"Jacky","family":"Guy","sequence":"first","affiliation":[{"name":"University of Edinburgh, Institute of Cell Biology, Michael Swann Building, Max Born Crescent, Edinburgh, EH9 3BF, 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