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Auteur A. BONNI |
Documents disponibles écrits par cet auteur (2)
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Cellular and molecular characterization of multiplex autism in human induced pluripotent stem cell-derived neurons / E. M. A. LEWIS in Molecular Autism, 10 (2019)
[article]
Titre : Cellular and molecular characterization of multiplex autism in human induced pluripotent stem cell-derived neurons Type de document : Texte imprimé et/ou numérique Auteurs : E. M. A. LEWIS, Auteur ; K. MEGANATHAN, Auteur ; D. BALDRIDGE, Auteur ; P. GONTARZ, Auteur ; B. ZHANG, Auteur ; A. BONNI, Auteur ; John N. CONSTANTINO, Auteur ; K. L. KROLL, Auteur Article en page(s) : 51 p. Langues : Anglais (eng) Mots-clés : Cortical excitatory neurons Cortical inhibitory neurons Gene networks Multiplex autism Neurodevelopment Transcriptomics iPSC modeling Index. décimale : PER Périodiques Résumé : Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder with pronounced heritability in the general population. This is largely attributable to the effects of polygenic susceptibility, with inherited liability exhibiting distinct sex differences in phenotypic expression. Attempts to model ASD in human cellular systems have principally involved rare de novo mutations associated with ASD phenocopies. However, by definition, these models are not representative of polygenic liability, which accounts for the vast share of population-attributable risk. Methods: Here, we performed what is, to our knowledge, the first attempt to model multiplex autism using patient-derived induced pluripotent stem cells (iPSCs) in a family manifesting incremental degrees of phenotypic expression of inherited liability (absent, intermediate, severe). The family members share an inherited variant of uncertain significance (VUS) in GPD2, a gene that was previously associated with developmental disability but here is insufficient by itself to cause ASD. iPSCs from three first-degree relatives and an unrelated control were differentiated into both cortical excitatory (cExN) and cortical inhibitory (cIN) neurons, and cellular phenotyping and transcriptomic analysis were conducted. Results: cExN neurospheres from the two affected individuals were reduced in size, compared to those derived from unaffected related and unrelated individuals. This reduction was, at least in part, due to increased apoptosis of cells from affected individuals upon initiation of cExN neural induction. Likewise, cIN neural progenitor cells from affected individuals exhibited increased apoptosis, compared to both unaffected individuals. Transcriptomic analysis of both cExN and cIN neural progenitor cells revealed distinct molecular signatures associated with affectation, including the misregulation of suites of genes associated with neural development, neuronal function, and behavior, as well as altered expression of ASD risk-associated genes. Conclusions: We have provided evidence of morphological, physiological, and transcriptomic signatures of polygenic liability to ASD from an analysis of cellular models derived from a multiplex autism family. ASD is commonly inherited on the basis of additive genetic liability. Therefore, identifying convergent cellular and molecular phenotypes resulting from polygenic and monogenic susceptibility may provide a critical bridge for determining which of the disparate effects of rare highly deleterious mutations might also apply to common autistic syndromes. En ligne : http://dx.doi.org/10.1186/s13229-019-0306-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=414
in Molecular Autism > 10 (2019) . - 51 p.[article] Cellular and molecular characterization of multiplex autism in human induced pluripotent stem cell-derived neurons [Texte imprimé et/ou numérique] / E. M. A. LEWIS, Auteur ; K. MEGANATHAN, Auteur ; D. BALDRIDGE, Auteur ; P. GONTARZ, Auteur ; B. ZHANG, Auteur ; A. BONNI, Auteur ; John N. CONSTANTINO, Auteur ; K. L. KROLL, Auteur . - 51 p.
Langues : Anglais (eng)
in Molecular Autism > 10 (2019) . - 51 p.
Mots-clés : Cortical excitatory neurons Cortical inhibitory neurons Gene networks Multiplex autism Neurodevelopment Transcriptomics iPSC modeling Index. décimale : PER Périodiques Résumé : Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder with pronounced heritability in the general population. This is largely attributable to the effects of polygenic susceptibility, with inherited liability exhibiting distinct sex differences in phenotypic expression. Attempts to model ASD in human cellular systems have principally involved rare de novo mutations associated with ASD phenocopies. However, by definition, these models are not representative of polygenic liability, which accounts for the vast share of population-attributable risk. Methods: Here, we performed what is, to our knowledge, the first attempt to model multiplex autism using patient-derived induced pluripotent stem cells (iPSCs) in a family manifesting incremental degrees of phenotypic expression of inherited liability (absent, intermediate, severe). The family members share an inherited variant of uncertain significance (VUS) in GPD2, a gene that was previously associated with developmental disability but here is insufficient by itself to cause ASD. iPSCs from three first-degree relatives and an unrelated control were differentiated into both cortical excitatory (cExN) and cortical inhibitory (cIN) neurons, and cellular phenotyping and transcriptomic analysis were conducted. Results: cExN neurospheres from the two affected individuals were reduced in size, compared to those derived from unaffected related and unrelated individuals. This reduction was, at least in part, due to increased apoptosis of cells from affected individuals upon initiation of cExN neural induction. Likewise, cIN neural progenitor cells from affected individuals exhibited increased apoptosis, compared to both unaffected individuals. Transcriptomic analysis of both cExN and cIN neural progenitor cells revealed distinct molecular signatures associated with affectation, including the misregulation of suites of genes associated with neural development, neuronal function, and behavior, as well as altered expression of ASD risk-associated genes. Conclusions: We have provided evidence of morphological, physiological, and transcriptomic signatures of polygenic liability to ASD from an analysis of cellular models derived from a multiplex autism family. ASD is commonly inherited on the basis of additive genetic liability. Therefore, identifying convergent cellular and molecular phenotypes resulting from polygenic and monogenic susceptibility may provide a critical bridge for determining which of the disparate effects of rare highly deleterious mutations might also apply to common autistic syndromes. En ligne : http://dx.doi.org/10.1186/s13229-019-0306-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=414 Complexities of X chromosome inactivation status in female human induced pluripotent stem cells-a brief review and scientific update for autism research / M. G. DANDULAKIS in Journal of Neurodevelopmental Disorders, 8-1 (December 2016)
[article]
Titre : Complexities of X chromosome inactivation status in female human induced pluripotent stem cells-a brief review and scientific update for autism research Type de document : Texte imprimé et/ou numérique Auteurs : M. G. DANDULAKIS, Auteur ; K. MEGANATHAN, Auteur ; K. L. KROLL, Auteur ; A. BONNI, Auteur ; John N. CONSTANTINO, Auteur Article en page(s) : p.22 Langues : Anglais (eng) Mots-clés : Asd Autism Developmental disorders X chromosome X-inactivation X-linked ASD X-reactivation iPSC "Female protective effect" Index. décimale : PER Périodiques Résumé : Induced pluripotent stem cells (iPSCs) allow researchers to make customized patient-derived cell lines by reprogramming noninvasively retrieved somatic cells. These cell lines have the potential to faithfully represent an individual's genetic background; therefore, in the absence of available human brain tissue from a living patient, these models have a significant advantage relative to other models of neurodevelopmental disease. When using human induced pluripotent stem cells (hiPSCs) to model X-linked developmental disorders or inherited conditions that undergo sex-specific modulation of penetrance (e.g., autism spectrum disorders), there are significant complexities in the course and status of X chromosome inactivation (XCI) that are crucial to consider in establishing the validity of cellular models. There are major gaps and inconsistencies in the existing literature regarding XCI status during the derivation and maintenance of hiPSCs and their differentiation into neurons. Here, we briefly describe the importance of the problem, review the findings and inconsistencies of the existing literature, delineate options for specifying XCI status in clonal populations, and develop recommendations for future studies. En ligne : http://dx.doi.org/10.1186/s11689-016-9155-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=348
in Journal of Neurodevelopmental Disorders > 8-1 (December 2016) . - p.22[article] Complexities of X chromosome inactivation status in female human induced pluripotent stem cells-a brief review and scientific update for autism research [Texte imprimé et/ou numérique] / M. G. DANDULAKIS, Auteur ; K. MEGANATHAN, Auteur ; K. L. KROLL, Auteur ; A. BONNI, Auteur ; John N. CONSTANTINO, Auteur . - p.22.
Langues : Anglais (eng)
in Journal of Neurodevelopmental Disorders > 8-1 (December 2016) . - p.22
Mots-clés : Asd Autism Developmental disorders X chromosome X-inactivation X-linked ASD X-reactivation iPSC "Female protective effect" Index. décimale : PER Périodiques Résumé : Induced pluripotent stem cells (iPSCs) allow researchers to make customized patient-derived cell lines by reprogramming noninvasively retrieved somatic cells. These cell lines have the potential to faithfully represent an individual's genetic background; therefore, in the absence of available human brain tissue from a living patient, these models have a significant advantage relative to other models of neurodevelopmental disease. When using human induced pluripotent stem cells (hiPSCs) to model X-linked developmental disorders or inherited conditions that undergo sex-specific modulation of penetrance (e.g., autism spectrum disorders), there are significant complexities in the course and status of X chromosome inactivation (XCI) that are crucial to consider in establishing the validity of cellular models. There are major gaps and inconsistencies in the existing literature regarding XCI status during the derivation and maintenance of hiPSCs and their differentiation into neurons. Here, we briefly describe the importance of the problem, review the findings and inconsistencies of the existing literature, delineate options for specifying XCI status in clonal populations, and develop recommendations for future studies. En ligne : http://dx.doi.org/10.1186/s11689-016-9155-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=348