A multi-model approach defines function altering MECP2 missense variants identified in individuals with autism spectrum disorder
MECP2 is commonly mutated in Rett syndrome, where MECP2s function as a DNA cytosine methylation reader is believed critical. MECP2 variants are also catalogued in individuals with autism spectrum disorder (ASD), including nine missense variants with no known clinical significance. To assess these nine as risk alleles for ASD, we developed MECP2 variant function assays using yeast, Drosophila and human cell lines. We calibrated these assays with known reference pathogenic and benign variants. Our data predict that four ASD variants are loss of function (LoF) and five are functional. Protein destabilization or nuclear delocalization offers insight into the altered function of a number of these variants. Notably, yeast and Drosophila lack DNA methylation, yet all Rett reference pathogenic and ASD variants in the methyl DNA binding domain that we analyzed proved to be LoF, suggesting a clinically-relevant role for non-methyl DNA-binding by MECP2.