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Eur J Hum Genet. 2015 Feb;23(2):195-201. doi: 10.1038/ejhg.2014.81. Epub 2014 Jun 11.

GluD1 is a common altered player in neuronal differentiation from both MECP2-mutated and CDKL5-mutated iPS cells.

Author information

1
Medical Genetics, University of Siena, Siena, Italy.
2
1] Medical Genetics, University of Siena, Siena, Italy [2] Department of Pharmacology, School of Medicine, University of California, Davis, Davis, CA, USA.
3
Department of Medical Microbiology and Immunology, University of California, Davis, Davis, USA.
4
Department of Neuroscience, University of Torino, Torino, Italy.
5
Department of Medical Biotechnology, University of Siena, Siena, Italy.
6
Department of Life Sciences, University of Siena, Siena, Italy.
7
1] Medical Genetics, University of Siena, Siena, Italy [2] Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
8
Department of Pharmacology, School of Medicine, University of California, Davis, Davis, CA, USA.

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.

PMID:
24916645
PMCID:
PMC4172451
DOI:
10.1038/ejhg.2014.81
[Indexed for MEDLINE]
Free PMC Article

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