Publication Date
8-10-2026
Journal
eLife
DOI
10.7554/eLife.109170
PMID
42573087
PMCID
PMC13456685
PubMedCentral® Posted Date
8-10-2026
PubMedCentral® Full Text Version
Post-print
Abstract
Mutations in the MECP2 gene cause the severe neurological disorder Rett syndrome. A cluster of frameshift-causing C-terminal deletions (CTDs) removes ~100 amino acids and accounts for approximately 10% of RTT-causing mutations. Their pathogenicity is unexpected because this C-terminal domain is dispensable in mice. Analysis of pathogenic and benign human MECP2 variants reveals that some individuals with apparently typical CTDs do not develop Rett syndrome, confirming that C-terminal truncations are not intrinsically pathogenic. Using human sequence data and mouse models we show that pathogenicity results from a marked reduction in MeCP2 levels and depends on the presence of a proline proline stop motif (-PPX) generated by a shift to the +2 reading frame. CTDs that shift to the +1 frame avoid this motif and are benign. Replacing the stop codon of the PPX motif with tryptophan restores MeCP2 expression and rescues RTT-like phenotypes in a CTD mouse model. An adenine base editor efficiently introduces this substitution in cultured cells. These findings define a reliable prognostic distinction between benign and pathogenic CTDs and establish a potential editing strategy for correcting disease-causing CTD mutations.
Keywords
Methyl-CpG-Binding Protein 2, Animals, Humans, Frameshift Mutation, Mice, Rett Syndrome, Disease Models, Animal, Sequence Deletion
Published Open-Access
yes
Recommended Citation
Guy, Jacky; Hein, Elena; Alexander-Howden, Beatrice; et al., "Translational Reading Frame Predicts the Pathogenicity of C-Terminal Frameshift Deletions in MeCP2" (2026). Duncan NRI Faculty and Staff Publications. 229.
https://digitalcommons.library.tmc.edu/duncar_nri_pub/229
Included in
Genetic Phenomena Commons, Medical Genetics Commons, Neurology Commons, Neurosciences Commons