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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 Genetic contributions to visuospatial cognition in Williams syndrome: insights from two contrasting partial deletion patients / H. BROADBENT in Journal of Neurodevelopmental Disorders, 6-1 (December 2014)
[article]
Titre : Genetic contributions to visuospatial cognition in Williams syndrome: insights from two contrasting partial deletion patients Type de document : Texte imprimé et/ou numérique Auteurs : H. BROADBENT, Auteur ; E. K. FARRAN, Auteur ; E. CHIN, Auteur ; K. METCALFE, Auteur ; M. TASSABEHJI, Auteur ; P. TURNPENNY, Auteur ; F. SANSBURY, Auteur ; E. MEABURN, Auteur ; Annette KARMILOFF-SMITH, Auteur Article en page(s) : p.18 Langues : Anglais (eng) Mots-clés : Gtf2i Gtf2ird1 Limk1 Navigation Visuospatial cognition Williams syndrome Index. décimale : PER Périodiques Résumé : BACKGROUND: Williams syndrome (WS) is a rare neurodevelopmental disorder arising from a hemizygotic deletion of approximately 27 genes on chromosome 7, at locus 7q11.23. WS is characterised by an uneven cognitive profile, with serious deficits in visuospatial tasks in comparison to relatively proficient performance in some other cognitive domains such as language and face processing. Individuals with partial genetic deletions within the WS critical region (WSCR) have provided insights into the contribution of specific genes to this complex phenotype. However, the combinatorial effects of different genes remain elusive. METHODS: WE REPORT ON VISUOSPATIAL COGNITION IN TWO INDIVIDUALS WITH CONTRASTING PARTIAL DELETIONS IN THE WSCR: one female (HR), aged 11 years 9 months, with haploinsufficiency for 24 of the WS genes (up to GTF2IRD1), and one male (JB), aged 14 years 2 months, with the three most telomeric genes within the WSCR deleted, or partially deleted. RESULTS: Our in-depth phenotyping of the visuospatial domain from table-top psychometric, and small- and large-scale experimental tasks reveal a profile in HR in line with typically developing controls, albeit with some atypical features. These data are contrasted with patient JB's atypical profile of strengths and weaknesses across the visuospatial domain, as well as with more substantial visuospatial deficits in individuals with the full WS deletion. CONCLUSIONS: Our findings point to the contribution of specific genes to spatial processing difficulties associated with WS, highlighting the multifaceted nature of spatial cognition and the divergent effects of genetic deletions within the WSCR on different components of visuospatial ability. The importance of general transcription factors at the telomeric end of the WSCR, and their combinatorial effects on the WS visuospatial phenotype are also discussed. En ligne : http://dx.doi.org/10.1186/1866-1955-6-18 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=346
in Journal of Neurodevelopmental Disorders > 6-1 (December 2014) . - p.18[article] Genetic contributions to visuospatial cognition in Williams syndrome: insights from two contrasting partial deletion patients [Texte imprimé et/ou numérique] / H. BROADBENT, Auteur ; E. K. FARRAN, Auteur ; E. CHIN, Auteur ; K. METCALFE, Auteur ; M. TASSABEHJI, Auteur ; P. TURNPENNY, Auteur ; F. SANSBURY, Auteur ; E. MEABURN, Auteur ; Annette KARMILOFF-SMITH, Auteur . - p.18.
Langues : Anglais (eng)
in Journal of Neurodevelopmental Disorders > 6-1 (December 2014) . - p.18
Mots-clés : Gtf2i Gtf2ird1 Limk1 Navigation Visuospatial cognition Williams syndrome Index. décimale : PER Périodiques Résumé : BACKGROUND: Williams syndrome (WS) is a rare neurodevelopmental disorder arising from a hemizygotic deletion of approximately 27 genes on chromosome 7, at locus 7q11.23. WS is characterised by an uneven cognitive profile, with serious deficits in visuospatial tasks in comparison to relatively proficient performance in some other cognitive domains such as language and face processing. Individuals with partial genetic deletions within the WS critical region (WSCR) have provided insights into the contribution of specific genes to this complex phenotype. However, the combinatorial effects of different genes remain elusive. METHODS: WE REPORT ON VISUOSPATIAL COGNITION IN TWO INDIVIDUALS WITH CONTRASTING PARTIAL DELETIONS IN THE WSCR: one female (HR), aged 11 years 9 months, with haploinsufficiency for 24 of the WS genes (up to GTF2IRD1), and one male (JB), aged 14 years 2 months, with the three most telomeric genes within the WSCR deleted, or partially deleted. RESULTS: Our in-depth phenotyping of the visuospatial domain from table-top psychometric, and small- and large-scale experimental tasks reveal a profile in HR in line with typically developing controls, albeit with some atypical features. These data are contrasted with patient JB's atypical profile of strengths and weaknesses across the visuospatial domain, as well as with more substantial visuospatial deficits in individuals with the full WS deletion. CONCLUSIONS: Our findings point to the contribution of specific genes to spatial processing difficulties associated with WS, highlighting the multifaceted nature of spatial cognition and the divergent effects of genetic deletions within the WSCR on different components of visuospatial ability. The importance of general transcription factors at the telomeric end of the WSCR, and their combinatorial effects on the WS visuospatial phenotype are also discussed. En ligne : http://dx.doi.org/10.1186/1866-1955-6-18 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=346