Abstract
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.
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Acknowledgements
We are grateful to A Bartolini for help with culture maintenance and differentiation. The work was partially funded by Telethon grant (GGP11110A), by Italian Health Ministry ‘Ricerca finalizzata 2008’ (RF-TOS-2008_1225570) and ‘Ricerca finalizzata 2010’ (RF-2010-2317597) grants, and by AIRETT (Associazione Italiana Rett) 2011 grant to AR. The ‘Cell lines and DNA bank of Rett Syndrome, X-linked mental retardation and other genetic diseases’, member of the Telethon Network of Genetic Biobanks (project no. GTB12001), funded by Telethon Italy, and of the EuroBioBank network, provided us with specimens.
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Livide, G., Patriarchi, T., Amenduni, M. et al. GluD1 is a common altered player in neuronal differentiation from both MECP2-mutated and CDKL5-mutated iPS cells. Eur J Hum Genet 23, 195–201 (2015). https://doi.org/10.1038/ejhg.2014.81
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DOI: https://doi.org/10.1038/ejhg.2014.81
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