Translational reading frame predicts the pathogenicity of C-terminal frameshift deletions in MeCP2
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…
Mutations in the MECP2 gene are responsible for the severe neurological disorder known as Rett syndrome. Approximately 10% of RTT-causing mutations are due to a specific type of frameshift-causing C-terminal deletions (CTDs) that remove around 100 amino acids. Despite the dispensability of the C-terminal domain in mice, these deletions are not inherently pathogenic. However, some individuals with apparent CTDs do not develop Rett syndrome, challenging the notion of their intrinsic pathogenicity.
Human sequence data and mouse models were analyzed to uncover the factors leading to pathogenicity. It was found that pathogenicity results from a significant reduction in MeCP2 levels, which 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, however, avoid this motif and are considered benign.
When the stop codon of the -PPX motif is replaced with tryptophan, MeCP2 expression is restored, and RTT-like phenotypes are rescued in a CTD mouse model.
The researchers also discovered that introducing this substitution using an adenine base editor in cultured cells could effectively correct disease-causing CTD mutations. These findings provide a reliable prognostic distinction between benign and pathogenic CTDs, opening the door to a potential editing strategy for treating patients with CTD mutations.
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