Effects of Rett syndrome mutations of the methyl-CpG binding domain of thetranscriptional repressor MeCP2 on selectivity for association with methylated DNA

We have investigated the properties of mutant forms of the methyl-CpG bindi ng transcriptional repressor MeCP2 associated with Rett syndrome, a childho od neurodevelopmental disorder. We find that four Rett syndrome mutations a t known sites within the methyl-CpG binding domain (MBD) impair binding to methylated DNA, but have little effect on nonspecific interactions with unm ethylated DNA. Three of these mutations (R106W, R133C, and F155S) have thei r binding affinities for methylated DNA reduced more than 100-fold; this is consistent with the hypothesis that impaired selectivity for methylated DN A of mutant MeCP2 contributes to Rett syndrome. However, a fourth mutant, T 158M, has its binding affinity for methylated DNA reduced only 2-fold, indi cative either of additional distinct regulatory functions associated with t he MBD or of an exquisite sensitivity of developing neurons to the selectiv e association of MeCP2 with methylated DNA.