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12 results on '"Alari, Valentina"'

3. Modeling RTT Syndrome by iPSC-Derived Neurons from Male and Female Patients with Heterogeneously Severe Hot-Spot MECP2 Variants

Author

Perego, Sara, primary, Alari, Valentina, additional, Pietra, Gianluca, additional, Lamperti, Andrea, additional, Vimercati, Alessandro, additional, Camporeale, Nicole, additional, Garzo, Maria, additional, Cogliati, Francesca, additional, Milani, Donatella, additional, Vignoli, Aglaia, additional, Peron, Angela, additional, Larizza, Lidia, additional, Pizzorusso, Tommaso, additional, and Russo, Silvia, additional

Published
2022
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6. Histone Deacetylase Inhibitors Ameliorate Morphological Defects and Hypoexcitability of iPSC-Neurons from Rubinstein-Taybi Patients

Author

Alari, Valentina, primary, Scalmani, Paolo, additional, Ajmone, Paola Francesca, additional, Perego, Sara, additional, Avignone, Sabrina, additional, Catusi, Ilaria, additional, Lonati, Paola Adele, additional, Borghi, Maria Orietta, additional, Finelli, Palma, additional, Terragni, Benedetta, additional, Mantegazza, Massimo, additional, Russo, Silvia, additional, and Larizza, Lidia, additional

Published
2021
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7. Transcriptome analysis of iPSC-derived neurons from Rubinstein-Taybi patients reveals deficits in neuronal differentiation

Author

Ministerio de Economía y Competitividad (España), Agencia Estatal de Investigación (España), Ministerio de Ciencia, Innovación y Universidades (España), European Commission, Generalitat Valenciana, Calzari, Luciano, Barcella, Matteo, Alari, Valentina, Braga, Daniele, Muñoz-Viana, Rafael, Barlassina, Cristina, Gervasini, Cristina, Barco, Ángel, Russo, Silvia, Larizza, Lidia, Ministerio de Economía y Competitividad (España), Agencia Estatal de Investigación (España), Ministerio de Ciencia, Innovación y Universidades (España), European Commission, Generalitat Valenciana, Calzari, Luciano, Barcella, Matteo, Alari, Valentina, Braga, Daniele, Muñoz-Viana, Rafael, Barlassina, Cristina, Gervasini, Cristina, Barco, Ángel, Russo, Silvia, and Larizza, Lidia

Abstract

Rubinstein-Taybi syndrome (RSTS) is a rare multisystem developmental disorder with moderate to severe intellectual disability caused by heterozygous mutations of either CREBBP or EP300 genes encoding CBP/p300 chromatin regulators. We explored the gene programs and processes underlying the morphological and functional alterations shown by iPSC-derived neurons modeling RSTS to bridge the molecular changes resulting from defective CBP/p300 to cognitive impairment. By global transcriptome analysis, we compared the differentially expressed genes (DEGs) marking the transition from iPSC-derived neural progenitors to cortical neurons (iNeurons) of five RSTS patients carrying private CREBBP/EP300 mutations and manifesting differently graded neurocognitive signs with those of four healthy controls. Our data shows a defective and altered neuroprogenitor to neuron transcriptional program in the cells from RSTS patients. First, transcriptional regulation is weaker in RSTS as less genes than in controls are modulated, including genes of key processes of mature functional neurons, such as those for voltage-gated channels and neurotransmitters and their receptors. Second, regulation is subverted as genes acting at pre-terminal stages of neural differentiation in cell polarity and adhesive functions (members of the cadherin family) and axon extension/guidance (members of the semaphorins and SLIT receptors families) are improperly upregulated. Impairment or delay of RSTS neuronal differentiation program is also evidenced by decreased modulation of the overall number of neural differentiation markers, significantly impacting the initial and final stages of the differentiation cascade. Last, extensive downregulation of genes for RNA/DNA metabolic processes confirms that RSTS is a global transcription disorder, consistent with a syndrome driven by chromatin dysregulation. Interestingly, the morphological and functional alterations we have previously appointed as biomarkers of RSTS iNeur

Published
2020

10. Generation of three iPSC lines (IAIi002, IAIi004, IAIi003) from Rubinstein-Taybi syndrome 1 patients carrying CREBBP non sense c.4435G>T, p.(Gly1479*) and c.3474G>A, p.(Trp1158*) and missense c.4627G>T, p.(Asp1543Tyr) mutations

Author

Alari, Valentina, primary, Russo, Silvia, additional, Rovina, Davide, additional, Garzo, Maria, additional, Crippa, Milena, additional, Calzari, Luciano, additional, Scalera, Claudia, additional, Concolino, Daniela, additional, Castiglioni, Elisa, additional, Giardino, Daniela, additional, Prosperi, Ennio, additional, Finelli, Palma, additional, Gervasini, Cristina, additional, Gowran, Aoife, additional, and Larizza, Lidia, additional

Published
2019
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11. Generation of the Rubinstein-Taybi syndrome type 2 patient-derived induced pluripotent stem cell line (IAIi001-A) carrying the EP300 exon 23 stop mutation c.3829A > T, p.(Lys1277*)

Author

Alari, Valentina, primary, Russo, Silvia, additional, Rovina, Davide, additional, Gowran, Aoife, additional, Garzo, Maria, additional, Crippa, Milena, additional, Mazzanti, Laura, additional, Scalera, Claudia, additional, Prosperi, Ennio, additional, Giardino, Daniela, additional, Gervasini, Cristina, additional, Finelli, Palma, additional, Pompilio, Giulio, additional, and Larizza, Lidia, additional

Published
2018
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12. Modeling RTT Syndrome by iPSC-Derived Neurons from Male and Female Patients with Heterogeneously Severe Hot-Spot MECP2 Variants

Author

Sara Perego, Valentina Alari, Gianluca Pietra, Andrea Lamperti, Alessandro Vimercati, Nicole Camporeale, Maria Garzo, Francesca Cogliati, Donatella Milani, Aglaia Vignoli, Angela Peron, Lidia Larizza, Tommaso Pizzorusso, Silvia Russo, Perego, Sara, Alari, Valentina, Pietra, Gianluca, Lamperti, Andrea, Vimercati, Alessandro, Camporeale, Nicole, Garzo, Maria, Cogliati, Francesca, Milani, Donatella, Vignoli, Aglaia, Peron, Angela, Larizza, Lidia, Pizzorusso, Tommaso, and Russo, Silvia

Subjects
Male, Neurons, early morphological neuronal biomarker, Organic Chemistry, Induced Pluripotent Stem Cells, iPSC-neuron, General Medicine, genotype-phenotype correlation, Settore BIO/09 - Fisiologia, mature neuron e-recordings, Catalysis, Computer Science Applications, Inorganic Chemistry, X inactivation mosaicism, Rett syndrome, Phenotype, hot-spot MECP2 pathogenic variant, Rett Syndrome, hot-spot MECP2 pathogenic variants, iPSC-neurons, early morphological neuronal biomarkers, Humans, Female, Physical and Theoretical Chemistry, Molecular Biology, Spectroscopy
Abstract

Rett syndrome caused by MECP2 variants is characterized by a heterogenous clinical spectrum accounted for in 60% of cases by hot-spot variants. Focusing on the most frequent variants, we generated in vitro iPSC-neurons from the blood of RTT girls with p.Arg133Cys and p.Arg255*, associated to mild and severe phenotype, respectively, and of an RTT male harboring the close to p.Arg255*, p.Gly252Argfs*7 variant. Truncated MeCP2 proteins were revealed by Western blot and immunofluorescence analysis. We compared the mutant versus control neurons at 42 days for morphological parameters and at 120 days for electrophysiology recordings, including girls’ isogenic clones. A precocious reduced morphological complexity was evident in neurons with truncating variants, while in p.Arg133Cys neurons any significant differences were observed in comparison with the isogenic wild-type clones. Reduced nuclear size and branch number show up as the most robust biomarkers. Patch clamp recordings on mature neurons allowed the assessment of cell biophysical properties, V-gated currents, and spiking pattern in the mutant and control cells. Immature spiking, altered cell capacitance, and membrane resistance of RTT neurons, were particularly pronounced in the Arg255* and Gly252Argfs*7 mutants. The overall results indicate that the specific markers of in vitro cellular phenotype mirror the clinical severity and may be amenable to drug testing for translational purposes.

Published
2022
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