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Autism Spectrum Symptomatology Among Children with Duplication 7q11.23 Syndrome / B. P. KLEIN-TASMAN in Journal of Autism and Developmental Disorders, 48-6 (June 2018)
[article]
Titre : Autism Spectrum Symptomatology Among Children with Duplication 7q11.23 Syndrome Type de document : Texte imprimé et/ou numérique Auteurs : B. P. KLEIN-TASMAN, Auteur ; C. B. MERVIS, Auteur Article en page(s) : p.1982-1994 Langues : Anglais (eng) Mots-clés : 7q11.23 duplication syndrome Autism spectrum disorders Selective mutism Social anxiety Index. décimale : PER Périodiques Résumé : Gold-standard diagnostic assessments of autism spectrum disorder (ASD) symptomatology were conducted on 63 children (mean CA: 8.81 years) with 7q11.23 duplication syndrome, one of the copy number variants identified by Sanders et al. (Neuron 70:863-885, 2011a) as associated with ASD. ASD classification rate was 39.6% for the Autism Diagnostic Interview-Revised and 25.4% for the Autism Diagnostic Observation Schedule-2 (ADOS-2). Based on these assessments combined with clinical judgment, 19.0% of children were diagnosed with ASD. Reasons for these discrepancies are discussed, as are differences in rate of diagnosis as a function of sex, age, and ADOS-2 module administered and differences in intellectual and adaptive behavior abilities as a function of presence or absence of ASD diagnosis and ADOS-2 module administered. Implications are addressed. En ligne : http://dx.doi.org/10.1007/s10803-017-3439-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=361
in Journal of Autism and Developmental Disorders > 48-6 (June 2018) . - p.1982-1994[article] Autism Spectrum Symptomatology Among Children with Duplication 7q11.23 Syndrome [Texte imprimé et/ou numérique] / B. P. KLEIN-TASMAN, Auteur ; C. B. MERVIS, Auteur . - p.1982-1994.
Langues : Anglais (eng)
in Journal of Autism and Developmental Disorders > 48-6 (June 2018) . - p.1982-1994
Mots-clés : 7q11.23 duplication syndrome Autism spectrum disorders Selective mutism Social anxiety Index. décimale : PER Périodiques Résumé : Gold-standard diagnostic assessments of autism spectrum disorder (ASD) symptomatology were conducted on 63 children (mean CA: 8.81 years) with 7q11.23 duplication syndrome, one of the copy number variants identified by Sanders et al. (Neuron 70:863-885, 2011a) as associated with ASD. ASD classification rate was 39.6% for the Autism Diagnostic Interview-Revised and 25.4% for the Autism Diagnostic Observation Schedule-2 (ADOS-2). Based on these assessments combined with clinical judgment, 19.0% of children were diagnosed with ASD. Reasons for these discrepancies are discussed, as are differences in rate of diagnosis as a function of sex, age, and ADOS-2 module administered and differences in intellectual and adaptive behavior abilities as a function of presence or absence of ASD diagnosis and ADOS-2 module administered. Implications are addressed. En ligne : http://dx.doi.org/10.1007/s10803-017-3439-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=361 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)
[article]
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
in Molecular Autism > 11 (2020)[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