Copy number variants (CNVs): a powerful tool for iPSC-based modelling of ASD / Danijela DRAKULIC in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 42 p. Titre : Copy number variants (CNVs): a powerful tool for iPSC-based modelling of ASD Type de document : Texte imprimé et/ou numérique Auteurs : Danijela DRAKULIC, Auteur ; Srdjan DJUROVIC, Auteur ; Yasir Ahmed SYED, Auteur ; Sebastiano TRATTARO, Auteur ; Nicolò CAPORALE, Auteur ; Anna FALK, Auteur ; Rivka OFIR, Auteur ; Vivi M. HEINE, Auteur ; Samuel J. R. A. CHAWNER, Auteur ; Antonio RODRIGUEZ-MORENO, Auteur ; Marianne B. M. VAN DEN BREE, Auteur ; Giuseppe TESTA, Auteur ; Spyros PETRAKIS, Auteur ; Adrian J. HARWOOD, Auteur Article en page(s) : 42 p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorders (ASD)  Copy number variants (CNVs)  Human iPSCs  Neurodevelopmental disorders (NDD) Index. décimale : PER Périodiques Résumé : Patients diagnosed with chromosome microdeletions or duplications, known as copy number variants (CNVs), present a unique opportunity to investigate the relationship between patient genotype and cell phenotype. CNVs have high genetic penetrance and give a good correlation between gene locus and patient clinical phenotype. This is especially effective for the study of patients with neurodevelopmental disorders (NDD), including those falling within the autism spectrum disorders (ASD). A key question is whether this correlation between genetics and clinical presentation at the level of the patient can be translated to the cell phenotypes arising from the neurodevelopment of patient induced pluripotent stem cells (iPSCs).Here, we examine how iPSCs derived from ASD patients with an associated CNV inform our understanding of the genetic and biological mechanisms underlying the aetiology of ASD. We consider selection of genetically characterised patient iPSCs; use of appropriate control lines; aspects of human neurocellular biology that can capture in vitro the patient clinical phenotype; and current limitations of patient iPSC-based studies. Finally, we consider how future research may be enhanced to maximise the utility of CNV patients for research of pathological mechanisms or therapeutic targets. En ligne : http://dx.doi.org/10.1186/s13229-020-00343-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 [article] Copy number variants (CNVs): a powerful tool for iPSC-based modelling of ASD [Texte imprimé et/ou numérique] / Danijela DRAKULIC, Auteur ; Srdjan DJUROVIC, Auteur ; Yasir Ahmed SYED, Auteur ; Sebastiano TRATTARO, Auteur ; Nicolò CAPORALE, Auteur ; Anna FALK, Auteur ; Rivka OFIR, Auteur ; Vivi M. HEINE, Auteur ; Samuel J. R. A. CHAWNER, Auteur ; Antonio RODRIGUEZ-MORENO, Auteur ; Marianne B. M. VAN DEN BREE, Auteur ; Giuseppe TESTA, Auteur ; Spyros PETRAKIS, Auteur ; Adrian J. HARWOOD, Auteur . - 42 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 42 p. Mots-clés : Autism spectrum disorders (ASD)  Copy number variants (CNVs)  Human iPSCs  Neurodevelopmental disorders (NDD) Index. décimale : PER Périodiques Résumé : Patients diagnosed with chromosome microdeletions or duplications, known as copy number variants (CNVs), present a unique opportunity to investigate the relationship between patient genotype and cell phenotype. CNVs have high genetic penetrance and give a good correlation between gene locus and patient clinical phenotype. This is especially effective for the study of patients with neurodevelopmental disorders (NDD), including those falling within the autism spectrum disorders (ASD). A key question is whether this correlation between genetics and clinical presentation at the level of the patient can be translated to the cell phenotypes arising from the neurodevelopment of patient induced pluripotent stem cells (iPSCs).Here, we examine how iPSCs derived from ASD patients with an associated CNV inform our understanding of the genetic and biological mechanisms underlying the aetiology of ASD. We consider selection of genetically characterised patient iPSCs; use of appropriate control lines; aspects of human neurocellular biology that can capture in vitro the patient clinical phenotype; and current limitations of patient iPSC-based studies. Finally, we consider how future research may be enhanced to maximise the utility of CNV patients for research of pathological mechanisms or therapeutic targets. En ligne : http://dx.doi.org/10.1186/s13229-020-00343-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427

High-throughput screening identifies histone deacetylase inhibitors that modulate GTF2I expression in 7q11.23 microduplication autism spectrum disorder patient-derived cortical neurons / Francesca CAVALLO in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) Titre : High-throughput screening identifies histone deacetylase inhibitors that modulate GTF2I expression in 7q11.23 microduplication autism spectrum disorder patient-derived cortical neurons Type de document : Texte imprimé et/ou numérique Auteurs : Francesca CAVALLO, Auteur ; Flavia TROGLIO, Auteur ; Giovanni FAGÀ, Auteur ; Daniele FANCELLI, Auteur ; Reinald SHYTI, Auteur ; Sebastiano TRATTARO, Auteur ; Matteo ZANELLA, Auteur ; Giuseppe D'AGOSTINO, Auteur ; James M. HUGHES, Auteur ; Maria Rosaria CERA, Auteur ; Maurizio PASI, Auteur ; Michele GABRIELE, Auteur ; Maddalena LAZZARIN, Auteur ; Marija MIHAILOVICH, Auteur ; Frank KOOY, Auteur ; Alessandro ROSA, Auteur ; Ciro MERCURIO, Auteur ; Mario VARASI, Auteur ; Giuseppe TESTA, Auteur Langues : Anglais (eng) Mots-clés : 7q11.23 duplication syndrome  Autism spectrum disorder  Gtf2i  HDAC inhibitors  High-throughput screening  Induced pluripotent stem cells  Intellectual disability  Neurons Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) is a highly prevalent neurodevelopmental condition affecting almost 1% of children, and represents a major unmet medical need with no effective drug treatment available. Duplication at 7q11.23 (7Dup), encompassing 26-28 genes, is one of the best characterized ASD-causing copy number variations and offers unique translational opportunities, because the hemideletion of the same interval causes Williams-Beuren syndrome (WBS), a condition defined by hypersociability and language strengths, thereby providing a unique reference to validate treatments for the ASD symptoms. In the above-indicated interval at 7q11.23, defined as WBS critical region, several genes, such as GTF2I, BAZ1B, CLIP2 and EIF4H, emerged as critical for their role in the pathogenesis of WBS and 7Dup both from mouse models and human studies. METHODS: We performed a high-throughput screening of 1478 compounds, including central nervous system agents, epigenetic modulators and experimental substances, on patient-derived cortical glutamatergic neurons differentiated from our cohort of induced pluripotent stem cell lines (iPSCs), monitoring the transcriptional modulation of WBS interval genes, with a special focus on GTF2I, in light of its overriding pathogenic role. The hits identified were validated by measuring gene expression by qRT-PCR and the results were confirmed by western blotting. RESULTS: We identified and selected three histone deacetylase inhibitors (HDACi) that decreased the abnormal expression level of GTF2I in 7Dup cortical glutamatergic neurons differentiated from four genetically different iPSC lines. We confirmed this effect also at the protein level. LIMITATIONS: In this study, we did not address the molecular mechanisms whereby HDAC inhibitors act on GTF2I. The lead compounds identified will now need to be advanced to further testing in additional models, including patient-derived brain organoids and mouse models recapitulating the gene imbalances of the 7q11.23 microduplication, in order to validate their efficacy in rescuing phenotypes across multiple functional layers within a translational pipeline towards clinical use. CONCLUSIONS: These results represent a unique opportunity for the development of a specific class of compounds for treating 7Dup and other forms of intellectual disability and autism. En ligne : http://dx.doi.org/10.1186/s13229-020-00387-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=438 [article] High-throughput screening identifies histone deacetylase inhibitors that modulate GTF2I expression in 7q11.23 microduplication autism spectrum disorder patient-derived cortical neurons [Texte imprimé et/ou numérique] / Francesca CAVALLO, Auteur ; Flavia TROGLIO, Auteur ; Giovanni FAGÀ, Auteur ; Daniele FANCELLI, Auteur ; Reinald SHYTI, Auteur ; Sebastiano TRATTARO, Auteur ; Matteo ZANELLA, Auteur ; Giuseppe D'AGOSTINO, Auteur ; James M. HUGHES, Auteur ; Maria Rosaria CERA, Auteur ; Maurizio PASI, Auteur ; Michele GABRIELE, Auteur ; Maddalena LAZZARIN, Auteur ; Marija MIHAILOVICH, Auteur ; Frank KOOY, Auteur ; Alessandro ROSA, Auteur ; Ciro MERCURIO, Auteur ; Mario VARASI, Auteur ; Giuseppe TESTA, Auteur. Langues : Anglais (eng) in Molecular Autism > 11 (2020) Mots-clés : 7q11.23 duplication syndrome  Autism spectrum disorder  Gtf2i  HDAC inhibitors  High-throughput screening  Induced pluripotent stem cells  Intellectual disability  Neurons Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) is a highly prevalent neurodevelopmental condition affecting almost 1% of children, and represents a major unmet medical need with no effective drug treatment available. Duplication at 7q11.23 (7Dup), encompassing 26-28 genes, is one of the best characterized ASD-causing copy number variations and offers unique translational opportunities, because the hemideletion of the same interval causes Williams-Beuren syndrome (WBS), a condition defined by hypersociability and language strengths, thereby providing a unique reference to validate treatments for the ASD symptoms. In the above-indicated interval at 7q11.23, defined as WBS critical region, several genes, such as GTF2I, BAZ1B, CLIP2 and EIF4H, emerged as critical for their role in the pathogenesis of WBS and 7Dup both from mouse models and human studies. METHODS: We performed a high-throughput screening of 1478 compounds, including central nervous system agents, epigenetic modulators and experimental substances, on patient-derived cortical glutamatergic neurons differentiated from our cohort of induced pluripotent stem cell lines (iPSCs), monitoring the transcriptional modulation of WBS interval genes, with a special focus on GTF2I, in light of its overriding pathogenic role. The hits identified were validated by measuring gene expression by qRT-PCR and the results were confirmed by western blotting. RESULTS: We identified and selected three histone deacetylase inhibitors (HDACi) that decreased the abnormal expression level of GTF2I in 7Dup cortical glutamatergic neurons differentiated from four genetically different iPSC lines. We confirmed this effect also at the protein level. LIMITATIONS: In this study, we did not address the molecular mechanisms whereby HDAC inhibitors act on GTF2I. The lead compounds identified will now need to be advanced to further testing in additional models, including patient-derived brain organoids and mouse models recapitulating the gene imbalances of the 7q11.23 microduplication, in order to validate their efficacy in rescuing phenotypes across multiple functional layers within a translational pipeline towards clinical use. CONCLUSIONS: These results represent a unique opportunity for the development of a specific class of compounds for treating 7Dup and other forms of intellectual disability and autism. En ligne : http://dx.doi.org/10.1186/s13229-020-00387-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=438

The sociability spectrum: evidence from reciprocal genetic copy number variations / Alejandro LÓPEZ-TOBÓN in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 50 p. Titre : The sociability spectrum: evidence from reciprocal genetic copy number variations Type de document : Texte imprimé et/ou numérique Auteurs : Alejandro LÓPEZ-TOBÓN, Auteur ; Sebastiano TRATTARO, Auteur ; Giuseppe TESTA, Auteur Article en page(s) : 50 p. Langues : Anglais (eng) Mots-clés : 7dupASD  7q11.23  Autism spectrum disorders  Hypersociability  Sociability  William-Beuren syndrome  iPSCs Index. décimale : PER Périodiques Résumé : Sociability entails some of the most complex behaviors processed by the central nervous system. It includes the detection, integration, and interpretation of social cues and elaboration of context-specific responses that are quintessentially species-specific. There is an ever-growing accumulation of molecular associations to autism spectrum disorders (ASD), from causative genes to endophenotypes across multiple functional layers; these however, have rarely been put in context with the opposite manifestation featured in hypersociability syndromes. Genetic copy number variations (CNVs) allow to investigate the relationships between gene dosage and its corresponding phenotypes. In particular, CNVs of the 7q11.23 locus, which manifest diametrically opposite social behaviors, offer a privileged window to look into the molecular substrates underlying the developmental trajectories of the social brain. As by definition sociability is studied in humans postnatally, the developmental fluctuations causing social impairments have thus far remained a black box. Here, we review key evidence of molecular players involved at both ends of the sociability spectrum, focusing on genetic and functional associations of neuroendocrine regulators and synaptic transmission pathways. We then proceed to propose the existence of a molecular axis centered around the paradigmatic dosage imbalances at the 7q11.23 locus, regulating networks responsible for the development of social behavior in humans and highlight the key role that neurodevelopmental models from reprogrammed pluripotent cells will play for its understanding. En ligne : http://dx.doi.org/10.1186/s13229-020-00347-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 [article] The sociability spectrum: evidence from reciprocal genetic copy number variations [Texte imprimé et/ou numérique] / Alejandro LÓPEZ-TOBÓN, Auteur ; Sebastiano TRATTARO, Auteur ; Giuseppe TESTA, Auteur . - 50 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 50 p. Mots-clés : 7dupASD  7q11.23  Autism spectrum disorders  Hypersociability  Sociability  William-Beuren syndrome  iPSCs Index. décimale : PER Périodiques Résumé : Sociability entails some of the most complex behaviors processed by the central nervous system. It includes the detection, integration, and interpretation of social cues and elaboration of context-specific responses that are quintessentially species-specific. There is an ever-growing accumulation of molecular associations to autism spectrum disorders (ASD), from causative genes to endophenotypes across multiple functional layers; these however, have rarely been put in context with the opposite manifestation featured in hypersociability syndromes. Genetic copy number variations (CNVs) allow to investigate the relationships between gene dosage and its corresponding phenotypes. In particular, CNVs of the 7q11.23 locus, which manifest diametrically opposite social behaviors, offer a privileged window to look into the molecular substrates underlying the developmental trajectories of the social brain. As by definition sociability is studied in humans postnatally, the developmental fluctuations causing social impairments have thus far remained a black box. Here, we review key evidence of molecular players involved at both ends of the sociability spectrum, focusing on genetic and functional associations of neuroendocrine regulators and synaptic transmission pathways. We then proceed to propose the existence of a molecular axis centered around the paradigmatic dosage imbalances at the 7q11.23 locus, regulating networks responsible for the development of social behavior in humans and highlight the key role that neurodevelopmental models from reprogrammed pluripotent cells will play for its understanding. En ligne : http://dx.doi.org/10.1186/s13229-020-00347-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427

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