title: GluD1 is a common altered player in neuronal differentiation from both MECP2-mutated and CDKL5-mutated iPS cells.
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.
authors.affiliation: Medical Genetics, University of Siena, Siena, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Livide
authors.affiliation: 1] Medical Genetics, University of Siena, Siena, Italy [2] Department of Pharmacology, School of Medicine, University of California, Davis, Davis, CA, USA.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Patriarchi
authors.affiliation: Medical Genetics, University of Siena, Siena, Italy.
authors.forename: Mariangela
authors.initials: M
authors.lastname: Amenduni
authors.affiliation: Medical Genetics, University of Siena, Siena, Italy.
authors.forename: Sonia
authors.initials: S
authors.lastname: Amabile
authors.affiliation: Department of Medical Microbiology and Immunology, University of California, Davis, Davis, USA.
authors.forename: Dag
authors.initials: D
authors.lastname: Yasui
authors.affiliation: Department of Neuroscience, University of Torino, Torino, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Calcagno
authors.affiliation: Medical Genetics, University of Siena, Siena, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Lo Rizzo
authors.affiliation: Department of Medical Biotechnology, University of Siena, Siena, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: De Falco
authors.affiliation: Department of Life Sciences, University of Siena, Siena, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Ulivieri
authors.affiliation: Medical Genetics, University of Siena, Siena, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Ariani
authors.affiliation: 1] Medical Genetics, University of Siena, Siena, Italy [2] Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Mari
authors.affiliation: 1] Medical Genetics, University of Siena, Siena, Italy [2] Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
authors.forename: Maria Antonietta
authors.initials: MA
authors.lastname: Mencarelli
authors.affiliation: Department of Pharmacology, School of Medicine, University of California, Davis, Davis, CA, USA.
authors.forename: Johannes Wilhelm
authors.initials: JW
authors.lastname: Hell
authors.affiliation: 1] Medical Genetics, University of Siena, Siena, Italy [2] Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Renieri
authors.affiliation: Medical Genetics, University of Siena, Siena, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Meloni
mesh_terms: D002478:Cells, Cultured; D005260:Female; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D055495:Neurogenesis; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D017470:Receptors, Glutamate / Q000235:genetics* / Q000378:metabolism; D015518:Rett Syndrome / Q000235:genetics* / Q000378:metabolism
chemical_list: C497392:MECP2 protein, human; D051783:Methyl-CpG-Binding Protein 2; D017470:Receptors, Glutamate; C108929:glutamate receptor delta 1; D017346:Protein Serine-Threonine Kinases; C114482:CDKL5 protein, human