Rett syndrome is a monogenic disease due to de novo mutations in either MECP2 or 
CDKL5 genes. In spite of their involvement in the same disease, a functional 
interaction between the two genes has not been proven. MeCP2 is a 
transcriptional regulator; CDKL5 encodes for a kinase protein that might be 
involved in the regulation of gene expression. Therefore, we hypothesized that 
mutations affecting the two genes may lead to similar phenotypes by 
dysregulating the expression of common genes. To test this hypothesis we used 
induced pluripotent stem (iPS) cells derived from fibroblasts of one Rett 
patient with a MECP2 mutation (p.Arg306Cys) and two patients with mutations in 
CDKL5 (p.Gln347Ter and p.Thr288Ile). Expression profiling was performed in 
CDKL5-mutated cells and genes of interest were confirmed by real-time RT-PCR in 
both CDKL5- and MECP2-mutated cells. The only major change in gene expression 
common to MECP2- and CDKL5-mutated cells was for GRID1, encoding for glutamate 
D1 receptor (GluD1), a member of the δ-family of ionotropic glutamate receptors. 
GluD1 does not form AMPA or NMDA glutamate receptors. It acts like an adhesion 
molecule by linking the postsynaptic and presynaptic compartments, 
preferentially inducing the inhibitory presynaptic differentiation of cortical 
neurons. Our results demonstrate that GRID1 expression is downregulated in both 
MECP2- and CDKL5-mutated iPS cells and upregulated in neuronal precursors and 
mature neurons. These data provide novel insights into disease pathophysiology 
and identify possible new targets for therapeutic treatment of Rett syndrome.