Translational reading frame predicts the pathogenicity of C-terminal frameshift deletions in MeCP2.
- Open access
A +2 reading frame shift in MECP2 C-terminal deletions predicts pathogenicity, with a 10% mutation subset causing Rett syndrome through reduced MeCP2 levels.
- Why it matters: Understanding which C-terminal deletions are truly disease-causing helps improve diagnosis and avoid misclassification of benign variants, addressing a critical gap in Rett syndrome genetics.
- What they did: The study analyzed human and mouse data, identifying that pathogenicity depends on a proline-proline stop motif (-PPX) created by a +2 frame shift, and used gene editing to test this mechanism.
- The result: Replacing the -PPX motif with tryptophan restores MeCP2 expression and alleviates Rett-like symptoms in mice, offering a promising strategy for precise genetic correction.