6 recherche sur le mot-clé 'Neurodevelopmental Disorders/genetics'

Reflections on the genetics-first approach to advancements in molecular genetic and neurobiological research on neurodevelopmental disorders / Anne B. ARNETT in Journal of Neurodevelopmental Disorders, 13 (2021)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 13 (2021) Titre : Reflections on the genetics-first approach to advancements in molecular genetic and neurobiological research on neurodevelopmental disorders Type de document : texte imprimé Auteurs : Anne B. ARNETT, Auteur ; Tianyun WANG, Auteur ; Evan E. EICHLER, Auteur ; Raphael A. BERNIER, Auteur Langues : Anglais (eng) Mots-clés : Autism Spectrum Disorder/genetics  Genomics  Humans  Intellectual Disability/genetics  Molecular Biology  Neurodevelopmental Disorders/genetics  Excitatory/inhibitory  Genetics-first  Molecular genetics  Neurobiology  Neurodevelopmental disorders Index. décimale : PER Périodiques Résumé : BACKGROUND: Neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD) and intellectual disability (ID), are common diagnoses with highly heterogeneous phenotypes and etiology. The genetics-first approach to research on NDDs has led to the identification of hundreds of genes conferring risk for ASD, ID, and related symptoms. MAIN BODY: Although relatively few individuals with NDDs share likely gene-disruptive (LGD) mutations in the same gene, characterization of overlapping functions, protein networks, and temporospatial expression patterns among these genes has led to increased understanding of the neurobiological etiology of NDDs. This shift in focus away from single genes and toward broader gene-brain-behavior pathways has been accelerated by the development of publicly available transcriptomic databases, cell type-specific research methods, and sequencing of non-coding genomic regions. CONCLUSIONS: The genetics-first approach to research on NDDs has advanced the identification of critical protein function pathways and temporospatial expression patterns, expanding the impact of this research beyond individuals with single-gene mutations to the broader population of patients with NDDs. En ligne : https://dx.doi.org/10.1186/s11689-021-09371-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=574 [article] Reflections on the genetics-first approach to advancements in molecular genetic and neurobiological research on neurodevelopmental disorders [texte imprimé] / Anne B. ARNETT, Auteur ; Tianyun WANG, Auteur ; Evan E. EICHLER, Auteur ; Raphael A. BERNIER, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 13 (2021) Mots-clés : Autism Spectrum Disorder/genetics  Genomics  Humans  Intellectual Disability/genetics  Molecular Biology  Neurodevelopmental Disorders/genetics  Excitatory/inhibitory  Genetics-first  Molecular genetics  Neurobiology  Neurodevelopmental disorders Index. décimale : PER Périodiques Résumé : BACKGROUND: Neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD) and intellectual disability (ID), are common diagnoses with highly heterogeneous phenotypes and etiology. The genetics-first approach to research on NDDs has led to the identification of hundreds of genes conferring risk for ASD, ID, and related symptoms. MAIN BODY: Although relatively few individuals with NDDs share likely gene-disruptive (LGD) mutations in the same gene, characterization of overlapping functions, protein networks, and temporospatial expression patterns among these genes has led to increased understanding of the neurobiological etiology of NDDs. This shift in focus away from single genes and toward broader gene-brain-behavior pathways has been accelerated by the development of publicly available transcriptomic databases, cell type-specific research methods, and sequencing of non-coding genomic regions. CONCLUSIONS: The genetics-first approach to research on NDDs has advanced the identification of critical protein function pathways and temporospatial expression patterns, expanding the impact of this research beyond individuals with single-gene mutations to the broader population of patients with NDDs. En ligne : https://dx.doi.org/10.1186/s11689-021-09371-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=574

Shared developmental gait disruptions across two mouse models of neurodevelopmental disorders / Rachel M. RAHN in Journal of Neurodevelopmental Disorders, 13 (2021)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 13 (2021) Titre : Shared developmental gait disruptions across two mouse models of neurodevelopmental disorders Type de document : texte imprimé Auteurs : Rachel M. RAHN, Auteur ; Claire T. WEICHSELBAUM, Auteur ; David H. GUTMANN, Auteur ; Joseph D. DOUGHERTY, Auteur ; Susan E. MALONEY, Auteur Langues : Anglais (eng) Mots-clés : Animals  Disease Models, Animal  Gait  Humans  Mice  Neurodevelopmental Disorders/genetics  Neurofibromatosis Type 1  Williams Syndrome  neurodevelopmental disorders  precision medicine Index. décimale : PER Périodiques Résumé : BACKGROUND: Motor deficits such as abnormal gait are an underappreciated yet characteristic phenotype of many neurodevelopmental disorders (NDDs), including Williams Syndrome (WS) and Neurofibromatosis Type 1 (NF1). Compared to cognitive phenotypes, gait phenotypes are readily and comparably assessed in both humans and model organisms and are controlled by well-defined CNS circuits. Discovery of a common gait phenotype between NDDs might suggest shared cellular and molecular deficits and highlight simple outcome variables to potentially quantify longitudinal treatment efficacy in NDDs. METHODS: We characterized gait using the DigiGait assay in two different murine NDD models: the complete deletion (CD) mouse, which models hemizygous loss of the complete WS locus, and the Nf1(+/R681X) mouse, which models a NF1 patient-derived heterozygous germline NF1 mutation. Longitudinal data were collected across four developmental time points (postnatal days 21-30) and one early adulthood time point. RESULTS: Compared to wildtype littermate controls, both models displayed markedly similar spatial, temporal, and postural gait abnormalities during development. Developing CD mice also displayed significant decreases in variability metrics. Multiple gait abnormalities observed across development in the Nf1(+/R681X) mice persisted into early adulthood, including increased stride length and decreased stride frequency, while developmental abnormalities in the CD model largely resolved by adulthood. CONCLUSIONS: These findings suggest that the subcomponents of gait affected in NDDs show overlap between disorders as well as some disorder-specific features, which may change over the course of development. Our incorporation of spatial, temporal, and postural gait measures also provides a template for gait characterization in other NDD models and a platform to examining circuits or longitudinal therapeutics. En ligne : https://dx.doi.org/10.1186/s11689-021-09359-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=573 [article] Shared developmental gait disruptions across two mouse models of neurodevelopmental disorders [texte imprimé] / Rachel M. RAHN, Auteur ; Claire T. WEICHSELBAUM, Auteur ; David H. GUTMANN, Auteur ; Joseph D. DOUGHERTY, Auteur ; Susan E. MALONEY, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 13 (2021) Mots-clés : Animals  Disease Models, Animal  Gait  Humans  Mice  Neurodevelopmental Disorders/genetics  Neurofibromatosis Type 1  Williams Syndrome  neurodevelopmental disorders  precision medicine Index. décimale : PER Périodiques Résumé : BACKGROUND: Motor deficits such as abnormal gait are an underappreciated yet characteristic phenotype of many neurodevelopmental disorders (NDDs), including Williams Syndrome (WS) and Neurofibromatosis Type 1 (NF1). Compared to cognitive phenotypes, gait phenotypes are readily and comparably assessed in both humans and model organisms and are controlled by well-defined CNS circuits. Discovery of a common gait phenotype between NDDs might suggest shared cellular and molecular deficits and highlight simple outcome variables to potentially quantify longitudinal treatment efficacy in NDDs. METHODS: We characterized gait using the DigiGait assay in two different murine NDD models: the complete deletion (CD) mouse, which models hemizygous loss of the complete WS locus, and the Nf1(+/R681X) mouse, which models a NF1 patient-derived heterozygous germline NF1 mutation. Longitudinal data were collected across four developmental time points (postnatal days 21-30) and one early adulthood time point. RESULTS: Compared to wildtype littermate controls, both models displayed markedly similar spatial, temporal, and postural gait abnormalities during development. Developing CD mice also displayed significant decreases in variability metrics. Multiple gait abnormalities observed across development in the Nf1(+/R681X) mice persisted into early adulthood, including increased stride length and decreased stride frequency, while developmental abnormalities in the CD model largely resolved by adulthood. CONCLUSIONS: These findings suggest that the subcomponents of gait affected in NDDs show overlap between disorders as well as some disorder-specific features, which may change over the course of development. Our incorporation of spatial, temporal, and postural gait measures also provides a template for gait characterization in other NDD models and a platform to examining circuits or longitudinal therapeutics. En ligne : https://dx.doi.org/10.1186/s11689-021-09359-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=573

An integrated clinical approach to children at genetic risk for neurodevelopmental and psychiatric conditions: interdisciplinary collaboration and research infrastructure / Jane SUMMERS in Journal of Neurodevelopmental Disorders, 16 (2024)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 16 (2024) Titre : An integrated clinical approach to children at genetic risk for neurodevelopmental and psychiatric conditions: interdisciplinary collaboration and research infrastructure Type de document : texte imprimé Auteurs : Jane SUMMERS, Auteur ; Danielle BARIBEAU, Auteur ; Polina PERLMAN, Auteur ; Ny HOANG, Auteur ; Sunny CUI, Auteur ; Aneta KRAKOWSKI, Auteur ; Patricia AMBROZEWICZ, Auteur ; Ariel HO, Auteur ; Thanuja SELVANAYAGAM, Auteur ; Kinga A. SÁNDOR-BAJUSZ, Auteur ; Katrina PALAD, Auteur ; Nishi PATEL, Auteur ; Sarah MCGAUGHEY, Auteur ; Louise GALLAGHER, Auteur ; Stephen W. SCHERER, Auteur ; Peter SZATMARI, Auteur ; Jacob VORSTMAN, Auteur Langues : Anglais (eng) Mots-clés : Humans  Child  Neurodevelopmental Disorders/genetics  Female  Male  Mental Disorders/genetics  Genetic Predisposition to Disease  Adolescent  Genetic disorder  Genetics  Interdisciplinary clinic  Mental health  Neurodevelopmental disorder  Psychiatry  Psychology  Research framework  speaker fees for Henry Stewart Talks Ltd. S.W.S. is on the Scientific Advisory  Committee of Population Bio, Deep Genomics, and serves as a Highly Cited Academic  Advisor for King Abdulaziz University. Intellectual property from aspects of his  research held at The Hospital for Sick Children are licensed to Athena  Diagnostics and Population Bio. D.B. has received research funding from MapLight  therapeutics. These relationships did not influence content of this manuscript  but are disclosed for potential future considerations. Index. décimale : PER Périodiques Résumé : BACKGROUND: A sizeable proportion of pathogenic genetic variants identified in young children tested for congenital differences are associated with neurodevelopmental psychiatric disorders (NPD). In this growing group, a genetic diagnosis often precedes the emergence of diagnosable developmental concerns. Here, we describe DAGSY (Developmental Assessment of Genetically Susceptible Youth), a novel interdisciplinary 'genetic-diagnosis-first' clinic integrating psychiatric, psychological and genetic expertise, and report our first observations and feedback from families and referring clinicians. METHODS: We retrieved data on referral sources and indications, genetic and NPD diagnoses and recommendations for children seen at DAGSY between 2018 and 2022. Through a survey, we obtained feedback from twenty families and eleven referring clinicians. RESULTS: 159 children (mean age 10.2 years, 57.2% males) completed an interdisciplinary (psychiatry, psychology, genetic counselling) DAGSY assessment during this period. Of these, 69.8% had a pathogenic microdeletion or microduplication, 21.5% a sequence-level variant, 4.4% a chromosomal disorder, and 4.4% a variant of unknown significance with emerging evidence of pathogenicity. One in four children did not have a prior NPD diagnosis, and referral to DAGSY was motivated by their genetic vulnerability alone. Following assessment, 76.7% received at least one new NPD diagnosis, most frequently intellectual disability (24.5%), anxiety (20.7%), autism spectrum (18.9%) and specific learning (16.4%) disorder. Both families and clinicians responding to our survey expressed satisfaction, but also highlighted some areas for potential improvement. CONCLUSIONS: DAGSY addresses an unmet clinical need for children identified with genetic variants that confer increased vulnerability for NPD and provides a crucial platform for research in this area. DAGSY can serve as a model for interdisciplinary clinics integrating child psychiatry, psychology and genetics, addressing both clinical and research needs for this emerging population. En ligne : https://dx.doi.org/10.1186/s11689-024-09552-x Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=575 [article] An integrated clinical approach to children at genetic risk for neurodevelopmental and psychiatric conditions: interdisciplinary collaboration and research infrastructure [texte imprimé] / Jane SUMMERS, Auteur ; Danielle BARIBEAU, Auteur ; Polina PERLMAN, Auteur ; Ny HOANG, Auteur ; Sunny CUI, Auteur ; Aneta KRAKOWSKI, Auteur ; Patricia AMBROZEWICZ, Auteur ; Ariel HO, Auteur ; Thanuja SELVANAYAGAM, Auteur ; Kinga A. SÁNDOR-BAJUSZ, Auteur ; Katrina PALAD, Auteur ; Nishi PATEL, Auteur ; Sarah MCGAUGHEY, Auteur ; Louise GALLAGHER, Auteur ; Stephen W. SCHERER, Auteur ; Peter SZATMARI, Auteur ; Jacob VORSTMAN, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 16 (2024) Mots-clés : Humans  Child  Neurodevelopmental Disorders/genetics  Female  Male  Mental Disorders/genetics  Genetic Predisposition to Disease  Adolescent  Genetic disorder  Genetics  Interdisciplinary clinic  Mental health  Neurodevelopmental disorder  Psychiatry  Psychology  Research framework  speaker fees for Henry Stewart Talks Ltd. S.W.S. is on the Scientific Advisory  Committee of Population Bio, Deep Genomics, and serves as a Highly Cited Academic  Advisor for King Abdulaziz University. Intellectual property from aspects of his  research held at The Hospital for Sick Children are licensed to Athena  Diagnostics and Population Bio. D.B. has received research funding from MapLight  therapeutics. These relationships did not influence content of this manuscript  but are disclosed for potential future considerations. Index. décimale : PER Périodiques Résumé : BACKGROUND: A sizeable proportion of pathogenic genetic variants identified in young children tested for congenital differences are associated with neurodevelopmental psychiatric disorders (NPD). In this growing group, a genetic diagnosis often precedes the emergence of diagnosable developmental concerns. Here, we describe DAGSY (Developmental Assessment of Genetically Susceptible Youth), a novel interdisciplinary 'genetic-diagnosis-first' clinic integrating psychiatric, psychological and genetic expertise, and report our first observations and feedback from families and referring clinicians. METHODS: We retrieved data on referral sources and indications, genetic and NPD diagnoses and recommendations for children seen at DAGSY between 2018 and 2022. Through a survey, we obtained feedback from twenty families and eleven referring clinicians. RESULTS: 159 children (mean age 10.2 years, 57.2% males) completed an interdisciplinary (psychiatry, psychology, genetic counselling) DAGSY assessment during this period. Of these, 69.8% had a pathogenic microdeletion or microduplication, 21.5% a sequence-level variant, 4.4% a chromosomal disorder, and 4.4% a variant of unknown significance with emerging evidence of pathogenicity. One in four children did not have a prior NPD diagnosis, and referral to DAGSY was motivated by their genetic vulnerability alone. Following assessment, 76.7% received at least one new NPD diagnosis, most frequently intellectual disability (24.5%), anxiety (20.7%), autism spectrum (18.9%) and specific learning (16.4%) disorder. Both families and clinicians responding to our survey expressed satisfaction, but also highlighted some areas for potential improvement. CONCLUSIONS: DAGSY addresses an unmet clinical need for children identified with genetic variants that confer increased vulnerability for NPD and provides a crucial platform for research in this area. DAGSY can serve as a model for interdisciplinary clinics integrating child psychiatry, psychology and genetics, addressing both clinical and research needs for this emerging population. En ligne : https://dx.doi.org/10.1186/s11689-024-09552-x Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=575

Behavioural and neurodevelopmental characteristics of SYNGAP1 / Nadja BEDNARCZUK in Journal of Neurodevelopmental Disorders, 16 (2024)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 16 (2024) Titre : Behavioural and neurodevelopmental characteristics of SYNGAP1 Type de document : texte imprimé Auteurs : Nadja BEDNARCZUK, Auteur ; Harriet HOUSBY, Auteur ; Irene O. LEE, Auteur ; Imagine CONSORTIUM, Auteur ; David SKUSE, Auteur ; Jeanne WOLSTENCROFT, Auteur Langues : Anglais (eng) Mots-clés : Humans  Female  ras GTPase-Activating Proteins/genetics  Male  Child  Adolescent  Child, Preschool  Intellectual Disability/genetics/etiology  Developmental Disabilities/genetics/etiology  United Kingdom  Neurodevelopmental Disorders/genetics  Cohort Studies  Phenotype  Epilepsy/genetics  Seizures/genetics  Autism  Behaviour  Intellectual Disability  Neurodevelopment  Syngap1 Index. décimale : PER Périodiques Résumé : BACKGROUND: SYNGAP1 variants are associated with varying degrees of intellectual disability (ID), developmental delay (DD), epilepsy, autism, and behavioural difficulties. These features may also be observed in other monogenic conditions. There is a need to systematically compare the characteristics of SYNGAP1 with other monogenic causes of ID and DD to identify features unique to the SYNAGP1 phenotype. We aimed to contrast the neurodevelopmental and behavioural phenotype of children with SYNGAP1-related ID (SYNGAP1-ID) to children with other monogenic conditions and a matched degree of ID. METHODS: Participants were identified from the IMAGINE-ID study, a UK-based, national cohort study of neuropsychiatric risk in children with ID of known genetic origin. Thirteen children with SYNGAP1 variants (age 4-16 years; 85% female) were matched (2:1) with 26 controls with other monogenic causes of ID for chronological and mental age, sex, socio-economic deprivation, adaptive behaviour, and physical health difficulties. Caregivers completed the Development and Wellbeing Assessment (DAWBA) and physical health questionnaires. RESULTS: Our results demonstrate that seizures affected children with SYNGAP1-ID (84.6%) more frequently than the ID-comparison group (7.6%; p = < 0.001). Fine-motor development was disproportionally impaired in SYNGAP1-ID, with 92.3% of children experiencing difficulties compared to 50% of ID-comparisons(p = 0.03). Gross motor and social development did not differ between the two groups. Children with SYNGAP1-ID were more likely to be non-verbal (61.5%) than ID-comparisons (23.1%; p = 0.01). Those children able to speak, spoke their first words at the same age as the ID-comparison group (mean = 3.25 years), yet achieved lower language competency (p = 0.04). Children with SYNGAP1-ID compared to the ID-comparison group were not more likely to meet criteria for autism (SYNGAP1-ID = 46.2%; ID-comparison = 30.7%; p = .35), attention-deficit hyperactivity disorder (15.4%;15.4%; p = 1), generalised anxiety (7.7%;15.4%; p = .49) or oppositional defiant disorder (7.7%;0%; p = .15). CONCLUSION: For the first time, we demonstrate that SYNGAP1-ID is associated with fine motor and language difficulties beyond those experienced by children with other genetic causes of DD and ID. Targeted occupational and speech and language therapies should be incorporated early into SYNGAP1-ID management. En ligne : https://dx.doi.org/10.1186/s11689-024-09563-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=575 [article] Behavioural and neurodevelopmental characteristics of SYNGAP1 [texte imprimé] / Nadja BEDNARCZUK, Auteur ; Harriet HOUSBY, Auteur ; Irene O. LEE, Auteur ; Imagine CONSORTIUM, Auteur ; David SKUSE, Auteur ; Jeanne WOLSTENCROFT, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 16 (2024) Mots-clés : Humans  Female  ras GTPase-Activating Proteins/genetics  Male  Child  Adolescent  Child, Preschool  Intellectual Disability/genetics/etiology  Developmental Disabilities/genetics/etiology  United Kingdom  Neurodevelopmental Disorders/genetics  Cohort Studies  Phenotype  Epilepsy/genetics  Seizures/genetics  Autism  Behaviour  Intellectual Disability  Neurodevelopment  Syngap1 Index. décimale : PER Périodiques Résumé : BACKGROUND: SYNGAP1 variants are associated with varying degrees of intellectual disability (ID), developmental delay (DD), epilepsy, autism, and behavioural difficulties. These features may also be observed in other monogenic conditions. There is a need to systematically compare the characteristics of SYNGAP1 with other monogenic causes of ID and DD to identify features unique to the SYNAGP1 phenotype. We aimed to contrast the neurodevelopmental and behavioural phenotype of children with SYNGAP1-related ID (SYNGAP1-ID) to children with other monogenic conditions and a matched degree of ID. METHODS: Participants were identified from the IMAGINE-ID study, a UK-based, national cohort study of neuropsychiatric risk in children with ID of known genetic origin. Thirteen children with SYNGAP1 variants (age 4-16 years; 85% female) were matched (2:1) with 26 controls with other monogenic causes of ID for chronological and mental age, sex, socio-economic deprivation, adaptive behaviour, and physical health difficulties. Caregivers completed the Development and Wellbeing Assessment (DAWBA) and physical health questionnaires. RESULTS: Our results demonstrate that seizures affected children with SYNGAP1-ID (84.6%) more frequently than the ID-comparison group (7.6%; p = < 0.001). Fine-motor development was disproportionally impaired in SYNGAP1-ID, with 92.3% of children experiencing difficulties compared to 50% of ID-comparisons(p = 0.03). Gross motor and social development did not differ between the two groups. Children with SYNGAP1-ID were more likely to be non-verbal (61.5%) than ID-comparisons (23.1%; p = 0.01). Those children able to speak, spoke their first words at the same age as the ID-comparison group (mean = 3.25 years), yet achieved lower language competency (p = 0.04). Children with SYNGAP1-ID compared to the ID-comparison group were not more likely to meet criteria for autism (SYNGAP1-ID = 46.2%; ID-comparison = 30.7%; p = .35), attention-deficit hyperactivity disorder (15.4%;15.4%; p = 1), generalised anxiety (7.7%;15.4%; p = .49) or oppositional defiant disorder (7.7%;0%; p = .15). CONCLUSION: For the first time, we demonstrate that SYNGAP1-ID is associated with fine motor and language difficulties beyond those experienced by children with other genetic causes of DD and ID. Targeted occupational and speech and language therapies should be incorporated early into SYNGAP1-ID management. En ligne : https://dx.doi.org/10.1186/s11689-024-09563-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=575

Disruption of grin2B, an ASD-associated gene, produces social deficits in zebrafish / Josiah D. ZOODSMA in Molecular Autism, 13 (2022)  

Public ISBD [article]  inMolecular Autism > 13 (2022) . - 38 p. Titre : Disruption of grin2B, an ASD-associated gene, produces social deficits in zebrafish Type de document : texte imprimé Auteurs : Josiah D. ZOODSMA, Auteur ; Emma J. KEEGAN, Auteur ; Gabrielle R. MOODY, Auteur ; Ashwin A. BHANDIWAD, Auteur ; Amalia J. NAPOLI, Auteur ; Harold A. BURGESS, Auteur ; Lonnie P. WOLLMUTH, Auteur ; Howard I. SIROTKIN, Auteur Article en page(s) : 38 p. Langues : Anglais (eng) Mots-clés : Animals  Codon, Nonsense  Glutamic Acid  Neurodevelopmental Disorders/genetics  Receptors, N-Methyl-D-Aspartate/genetics  Zebrafish/genetics  Autism spectrum disorders  GluN2B  NMDA receptors  Social behaviors Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD), like many neurodevelopmental disorders, has complex and varied etiologies. Advances in genome sequencing have identified multiple candidate genes associated with ASD, including dozens of missense and nonsense mutations in the NMDAR subunit GluN2B, encoded by GRIN2B. NMDARs are glutamate-gated ion channels with key synaptic functions in excitatory neurotransmission. How alterations in these proteins impact neurodevelopment is poorly understood, in part because knockouts of GluN2B in rodents are lethal. METHODS: Here, we use CRISPR-Cas9 to generate zebrafish lacking GluN2B (grin2B(-/-)). Using these fish, we run an array of behavioral tests and perform whole-brain larval imaging to assay developmental roles and functions of GluN2B. RESULTS: We demonstrate that zebrafish GluN2B displays similar structural and functional properties to human GluN2B. Zebrafish lacking GluN2B (grin2B(-/-)) surprisingly survive into adulthood. Given the prevalence of social deficits in ASD, we assayed social preference in the grin2B(-/-) fish. Wild-type fish develop a strong social preference by 3 weeks post fertilization. In contrast, grin2B(-/-) fish at this age exhibit significantly reduced social preference. Notably, the lack of GluN2B does not result in a broad disruption of neurodevelopment, as grin2B(-/-) larvae do not show alterations in spontaneous or photic-evoked movements, are capable of prey capture, and exhibit learning. Whole-brain imaging of grin2B(-/-) larvae revealed reduction of an inhibitory neuron marker in the subpallium, a region linked to ASD in humans, but showed that overall brain size and E/I balance in grin2B(-/-) is comparable to wild type. LIMITATIONS: Zebrafish lacking GluN2B, while useful in studying developmental roles of GluN2B, are unlikely to model nuanced functional alterations of human missense mutations that are not complete loss of function. Additionally, detailed mammalian homologies for larval zebrafish brain subdivisions at the age of whole-brain imaging are not fully resolved. CONCLUSIONS: We demonstrate that zebrafish completely lacking the GluN2B subunit of the NMDAR, unlike rodent models, are viable into adulthood. Notably, they exhibit a highly specific deficit in social behavior. As such, this zebrafish model affords a unique opportunity to study the roles of GluN2B in ASD etiologies and establish a disease-relevant in vivo model for future studies. En ligne : http://dx.doi.org/10.1186/s13229-022-00516-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=491 [article] Disruption of grin2B, an ASD-associated gene, produces social deficits in zebrafish [texte imprimé] / Josiah D. ZOODSMA, Auteur ; Emma J. KEEGAN, Auteur ; Gabrielle R. MOODY, Auteur ; Ashwin A. BHANDIWAD, Auteur ; Amalia J. NAPOLI, Auteur ; Harold A. BURGESS, Auteur ; Lonnie P. WOLLMUTH, Auteur ; Howard I. SIROTKIN, Auteur . - 38 p. Langues : Anglais (eng) in Molecular Autism > 13 (2022) . - 38 p. Mots-clés : Animals  Codon, Nonsense  Glutamic Acid  Neurodevelopmental Disorders/genetics  Receptors, N-Methyl-D-Aspartate/genetics  Zebrafish/genetics  Autism spectrum disorders  GluN2B  NMDA receptors  Social behaviors Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD), like many neurodevelopmental disorders, has complex and varied etiologies. Advances in genome sequencing have identified multiple candidate genes associated with ASD, including dozens of missense and nonsense mutations in the NMDAR subunit GluN2B, encoded by GRIN2B. NMDARs are glutamate-gated ion channels with key synaptic functions in excitatory neurotransmission. How alterations in these proteins impact neurodevelopment is poorly understood, in part because knockouts of GluN2B in rodents are lethal. METHODS: Here, we use CRISPR-Cas9 to generate zebrafish lacking GluN2B (grin2B(-/-)). Using these fish, we run an array of behavioral tests and perform whole-brain larval imaging to assay developmental roles and functions of GluN2B. RESULTS: We demonstrate that zebrafish GluN2B displays similar structural and functional properties to human GluN2B. Zebrafish lacking GluN2B (grin2B(-/-)) surprisingly survive into adulthood. Given the prevalence of social deficits in ASD, we assayed social preference in the grin2B(-/-) fish. Wild-type fish develop a strong social preference by 3 weeks post fertilization. In contrast, grin2B(-/-) fish at this age exhibit significantly reduced social preference. Notably, the lack of GluN2B does not result in a broad disruption of neurodevelopment, as grin2B(-/-) larvae do not show alterations in spontaneous or photic-evoked movements, are capable of prey capture, and exhibit learning. Whole-brain imaging of grin2B(-/-) larvae revealed reduction of an inhibitory neuron marker in the subpallium, a region linked to ASD in humans, but showed that overall brain size and E/I balance in grin2B(-/-) is comparable to wild type. LIMITATIONS: Zebrafish lacking GluN2B, while useful in studying developmental roles of GluN2B, are unlikely to model nuanced functional alterations of human missense mutations that are not complete loss of function. Additionally, detailed mammalian homologies for larval zebrafish brain subdivisions at the age of whole-brain imaging are not fully resolved. CONCLUSIONS: We demonstrate that zebrafish completely lacking the GluN2B subunit of the NMDAR, unlike rodent models, are viable into adulthood. Notably, they exhibit a highly specific deficit in social behavior. As such, this zebrafish model affords a unique opportunity to study the roles of GluN2B in ASD etiologies and establish a disease-relevant in vivo model for future studies. En ligne : http://dx.doi.org/10.1186/s13229-022-00516-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=491

Consistency of parent-report SLC6A1 data in Simons Searchlight with Provider-Based Publications / Jennifer M. BAIN in Journal of Neurodevelopmental Disorders, 14 (2022)  

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