40 recherche sur le mot-clé 'Molecular'

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

Assessing phenotypic and polygenic models of ADHD to identify mechanisms of risk for longitudinal trajectories of externalizing behaviors / James J. LI in Journal of Child Psychology and Psychiatry, 60-11 (November 2019)  

Public ISBD [article]  inJournal of Child Psychology and Psychiatry > 60-11 (November 2019) . - p.1191-1199 Titre : Assessing phenotypic and polygenic models of ADHD to identify mechanisms of risk for longitudinal trajectories of externalizing behaviors Type de document : texte imprimé Auteurs : James J. LI, Auteur Article en page(s) : p.1191-1199 Langues : Anglais (eng) Mots-clés : Adhd  antisocial behavior  longitudinal studies  mediation  molecular genetics Index. décimale : PER Périodiques Résumé : BACKGROUND: Children with ADHD frequently engage in higher rates of externalizing behaviors in adulthood relative to children without. However, externalizing behaviors vary across development. Little is known about how this risk unfolds across development. Phenotypic and polygenic models of childhood ADHD were used to predict individual differences in adult externalizing trajectories. Supportive parenting, school connectedness, and peer closeness were then examined as causal mechanisms. METHODS: Data were from the National Longitudinal Study of Adolescent to Adult Health (N = 7,674). Externalizing behavior was measured using data from age 18 to 32 and modeled using latent class growth analysis. Child ADHD was measured using retrospective self-report (phenotypic model) and genome-wide polygenic risk scores (polygenic model). Multiple mediation models examined the direct and indirect effects of the phenotypic and polygenic models (separately) on externalizing trajectories through the effects of adolescent supportive parenting, school connectedness, and peer closeness. RESULTS: Phenotypic and polygenic models of ADHD were associated with being in the High Decreasing (3.2% of sample) and Moderate (16.1%) adult externalizing trajectories, but not the severe Low Increasing trajectory (2.6%), relative to the Normal trajectory (78.2%). Associations between both models of ADHD on the High Decreasing and Moderate trajectories were partially mediated through the effects of school connectedness, but not supportive parenting or peer closeness. CONCLUSIONS: Findings shed light on how childhood ADHD affects downstream psychosocial processes that then predict specific externalizing outcomes in adulthood. They also reinforce the importance of fostering a strong school environment for adolescents with (and without) ADHD, as this context plays a critical role in shaping the development of externalizing behaviors in adulthood. En ligne : http://dx.doi.org/10.1111/jcpp.13071 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=408 [article] Assessing phenotypic and polygenic models of ADHD to identify mechanisms of risk for longitudinal trajectories of externalizing behaviors [texte imprimé] / James J. LI, Auteur . - p.1191-1199. Langues : Anglais (eng) in Journal of Child Psychology and Psychiatry > 60-11 (November 2019) . - p.1191-1199 Mots-clés : Adhd  antisocial behavior  longitudinal studies  mediation  molecular genetics Index. décimale : PER Périodiques Résumé : BACKGROUND: Children with ADHD frequently engage in higher rates of externalizing behaviors in adulthood relative to children without. However, externalizing behaviors vary across development. Little is known about how this risk unfolds across development. Phenotypic and polygenic models of childhood ADHD were used to predict individual differences in adult externalizing trajectories. Supportive parenting, school connectedness, and peer closeness were then examined as causal mechanisms. METHODS: Data were from the National Longitudinal Study of Adolescent to Adult Health (N = 7,674). Externalizing behavior was measured using data from age 18 to 32 and modeled using latent class growth analysis. Child ADHD was measured using retrospective self-report (phenotypic model) and genome-wide polygenic risk scores (polygenic model). Multiple mediation models examined the direct and indirect effects of the phenotypic and polygenic models (separately) on externalizing trajectories through the effects of adolescent supportive parenting, school connectedness, and peer closeness. RESULTS: Phenotypic and polygenic models of ADHD were associated with being in the High Decreasing (3.2% of sample) and Moderate (16.1%) adult externalizing trajectories, but not the severe Low Increasing trajectory (2.6%), relative to the Normal trajectory (78.2%). Associations between both models of ADHD on the High Decreasing and Moderate trajectories were partially mediated through the effects of school connectedness, but not supportive parenting or peer closeness. CONCLUSIONS: Findings shed light on how childhood ADHD affects downstream psychosocial processes that then predict specific externalizing outcomes in adulthood. They also reinforce the importance of fostering a strong school environment for adolescents with (and without) ADHD, as this context plays a critical role in shaping the development of externalizing behaviors in adulthood. En ligne : http://dx.doi.org/10.1111/jcpp.13071 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=408

Assessing the integrity of auditory sensory memory processing in CLN3 disease (Juvenile Neuronal Ceroid Lipofuscinosis (Batten disease)): an auditory evoked potential study of the duration-evoked mismatch negativity (MMN) / Tufikameni BRIMA in Journal of Neurodevelopmental Disorders, 16 (2024)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 16 (2024) Titre : Assessing the integrity of auditory sensory memory processing in CLN3 disease (Juvenile Neuronal Ceroid Lipofuscinosis (Batten disease)): an auditory evoked potential study of the duration-evoked mismatch negativity (MMN) Type de document : texte imprimé Auteurs : Tufikameni BRIMA, Auteur ; Edward G. FREEDMAN, Auteur ; Kevin D. PRINSLOO, Auteur ; Erika F. AUGUSTINE, Auteur ; Heather R. ADAMS, Auteur ; Kuan Hong WANG, Auteur ; Jonathan W. MINK, Auteur ; Luke H. SHAW, Auteur ; Emma P. MANTEL, Auteur ; John J. FOXE, Auteur Langues : Anglais (eng) Mots-clés : Humans  Neuronal Ceroid-Lipofuscinoses/complications  Auditory Perception  Evoked Potentials, Auditory  Memory  Brain  Membrane Glycoproteins  Molecular Chaperones  Eeg  Erp  Event-related potential  Jncl  Lysosomal storage disorder  Neurodegenerative disease  Neurodevelopmental disorder  would bias the work reported herein. Index. décimale : PER Périodiques Résumé : BACKGROUND: We interrogated auditory sensory memory capabilities in individuals with CLN3 disease (juvenile neuronal ceroid lipofuscinosis), specifically for the feature of "duration" processing. Given decrements in auditory processing abilities associated with later-stage CLN3 disease, we hypothesized that the duration-evoked mismatch negativity (MMN) of the event related potential (ERP) would be a marker of progressively atypical cortical processing in this population, with potential applicability as a brain-based biomarker in clinical trials. METHODS: We employed three stimulation rates (fast: 450 ms, medium: 900 ms, slow: 1800 ms), allowing for assessment of the sustainability of the auditory sensory memory trace. The robustness of MMN directly relates to the rate at which the regularly occurring stimulus stream is presented. As presentation rate slows, robustness of the sensory memory trace diminishes. By manipulating presentation rate, the strength of the sensory memory trace is parametrically varied, providing greater sensitivity to detect auditory cortical dysfunction. A secondary hypothesis was that duration-evoked MMN abnormalities in CLN3 disease would be more severe at slower presentation rates, resulting from greater demand on the sensory memory system. RESULTS: Data from individuals with CLN3 disease (N = 21; range 6-28 years of age) showed robust MMN responses (i.e., intact auditory sensory memory processes) at the medium stimulation rate. However, at the fastest rate, MMN was significantly reduced, and at the slowest rate, MMN was not detectable in CLN3 disease relative to neurotypical controls (N = 41; ages 6-26 years). CONCLUSIONS: Results reveal emerging insufficiencies in this critical auditory perceptual system in individuals with CLN3 disease. En ligne : https://dx.doi.org/10.1186/s11689-023-09515-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=575 [article] Assessing the integrity of auditory sensory memory processing in CLN3 disease (Juvenile Neuronal Ceroid Lipofuscinosis (Batten disease)): an auditory evoked potential study of the duration-evoked mismatch negativity (MMN) [texte imprimé] / Tufikameni BRIMA, Auteur ; Edward G. FREEDMAN, Auteur ; Kevin D. PRINSLOO, Auteur ; Erika F. AUGUSTINE, Auteur ; Heather R. ADAMS, Auteur ; Kuan Hong WANG, Auteur ; Jonathan W. MINK, Auteur ; Luke H. SHAW, Auteur ; Emma P. MANTEL, Auteur ; John J. FOXE, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 16 (2024) Mots-clés : Humans  Neuronal Ceroid-Lipofuscinoses/complications  Auditory Perception  Evoked Potentials, Auditory  Memory  Brain  Membrane Glycoproteins  Molecular Chaperones  Eeg  Erp  Event-related potential  Jncl  Lysosomal storage disorder  Neurodegenerative disease  Neurodevelopmental disorder  would bias the work reported herein. Index. décimale : PER Périodiques Résumé : BACKGROUND: We interrogated auditory sensory memory capabilities in individuals with CLN3 disease (juvenile neuronal ceroid lipofuscinosis), specifically for the feature of "duration" processing. Given decrements in auditory processing abilities associated with later-stage CLN3 disease, we hypothesized that the duration-evoked mismatch negativity (MMN) of the event related potential (ERP) would be a marker of progressively atypical cortical processing in this population, with potential applicability as a brain-based biomarker in clinical trials. METHODS: We employed three stimulation rates (fast: 450 ms, medium: 900 ms, slow: 1800 ms), allowing for assessment of the sustainability of the auditory sensory memory trace. The robustness of MMN directly relates to the rate at which the regularly occurring stimulus stream is presented. As presentation rate slows, robustness of the sensory memory trace diminishes. By manipulating presentation rate, the strength of the sensory memory trace is parametrically varied, providing greater sensitivity to detect auditory cortical dysfunction. A secondary hypothesis was that duration-evoked MMN abnormalities in CLN3 disease would be more severe at slower presentation rates, resulting from greater demand on the sensory memory system. RESULTS: Data from individuals with CLN3 disease (N = 21; range 6-28 years of age) showed robust MMN responses (i.e., intact auditory sensory memory processes) at the medium stimulation rate. However, at the fastest rate, MMN was significantly reduced, and at the slowest rate, MMN was not detectable in CLN3 disease relative to neurotypical controls (N = 41; ages 6-26 years). CONCLUSIONS: Results reveal emerging insufficiencies in this critical auditory perceptual system in individuals with CLN3 disease. En ligne : https://dx.doi.org/10.1186/s11689-023-09515-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=575

Combined polygenic risk scores of different psychiatric traits predict general and specific psychopathology in childhood / Alexander NEUMANN in Journal of Child Psychology and Psychiatry, 63-6 (June 2022)  

Public ISBD [article]  inJournal of Child Psychology and Psychiatry > 63-6 (June 2022) . - p.636-645 Titre : Combined polygenic risk scores of different psychiatric traits predict general and specific psychopathology in childhood Type de document : texte imprimé Auteurs : Alexander NEUMANN, Auteur ; Alexia JOLICOEUR-MARTINEAU, Auteur ; Eszter SZEKELY, Auteur ; Hannah M. SALLIS, Auteur ; Kieran O'DONNEL, Auteur ; Celia M.T. GREENWOOD, Auteur ; Robert LEVITAN, Auteur ; Michael J. MEANEY, Auteur ; Ashley WAZANA, Auteur ; Jonathan P. EVANS, Auteur ; Henning TIEMEIER, Auteur Article en page(s) : p.636-645 Langues : Anglais (eng) Mots-clés : Genetics  comorbidity  externalizing disorder  internalizing disorder  meta-analysis  molecular Index. décimale : PER Périodiques Résumé : BACKGROUND: Polygenic risk scores (PRSs) operationalize genetic propensity toward a particular mental disorder and hold promise as early predictors of psychopathology, but before a PRS can be used clinically, explanatory power must be increased and the specificity for a psychiatric domain established. To enable early detection, it is crucial to study these psychometric properties in childhood. We examined whether PRSs associate more with general or with specific psychopathology in school-aged children. Additionally, we tested whether psychiatric PRSs can be combined into a multi-PRS score for improved performance. METHODS: We computed 16 PRSs based on GWASs of psychiatric phenotypes, but also neuroticism and cognitive ability, in mostly adult populations. Study participants were 9,247 school-aged children from three population-based cohorts of the DREAM-BIG consortium: ALSPAC (UK), The Generation R Study (Netherlands), and MAVAN (Canada). We associated each PRS with general and specific psychopathology factors, derived from a bifactor model based on self-report and parental, teacher, and observer reports. After fitting each PRS in separate models, we also tested a multi-PRS model, in which all PRSs are entered simultaneously as predictors of the general psychopathology factor. RESULTS: Seven PRSs were associated with the general psychopathology factor after multiple testing adjustment, two with specific externalizing and five with specific internalizing psychopathology. PRSs predicted general psychopathology independently of each other, with the exception of depression and depressive symptom PRSs. Most PRSs associated with a specific psychopathology domain, were also associated with general child psychopathology. CONCLUSIONS: The results suggest that PRSs based on current GWASs of psychiatric phenotypes tend to be associated with general psychopathology, or both general and specific psychiatric domains, but not with one specific psychopathology domain only. Furthermore, PRSs can be combined to improve predictive ability. PRS users should therefore be conscious of nonspecificity and consider using multiple PRSs simultaneously, when predicting psychiatric disorders. En ligne : http://dx.doi.org/10.1111/jcpp.13501 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=475 [article] Combined polygenic risk scores of different psychiatric traits predict general and specific psychopathology in childhood [texte imprimé] / Alexander NEUMANN, Auteur ; Alexia JOLICOEUR-MARTINEAU, Auteur ; Eszter SZEKELY, Auteur ; Hannah M. SALLIS, Auteur ; Kieran O'DONNEL, Auteur ; Celia M.T. GREENWOOD, Auteur ; Robert LEVITAN, Auteur ; Michael J. MEANEY, Auteur ; Ashley WAZANA, Auteur ; Jonathan P. EVANS, Auteur ; Henning TIEMEIER, Auteur . - p.636-645. Langues : Anglais (eng) in Journal of Child Psychology and Psychiatry > 63-6 (June 2022) . - p.636-645 Mots-clés : Genetics  comorbidity  externalizing disorder  internalizing disorder  meta-analysis  molecular Index. décimale : PER Périodiques Résumé : BACKGROUND: Polygenic risk scores (PRSs) operationalize genetic propensity toward a particular mental disorder and hold promise as early predictors of psychopathology, but before a PRS can be used clinically, explanatory power must be increased and the specificity for a psychiatric domain established. To enable early detection, it is crucial to study these psychometric properties in childhood. We examined whether PRSs associate more with general or with specific psychopathology in school-aged children. Additionally, we tested whether psychiatric PRSs can be combined into a multi-PRS score for improved performance. METHODS: We computed 16 PRSs based on GWASs of psychiatric phenotypes, but also neuroticism and cognitive ability, in mostly adult populations. Study participants were 9,247 school-aged children from three population-based cohorts of the DREAM-BIG consortium: ALSPAC (UK), The Generation R Study (Netherlands), and MAVAN (Canada). We associated each PRS with general and specific psychopathology factors, derived from a bifactor model based on self-report and parental, teacher, and observer reports. After fitting each PRS in separate models, we also tested a multi-PRS model, in which all PRSs are entered simultaneously as predictors of the general psychopathology factor. RESULTS: Seven PRSs were associated with the general psychopathology factor after multiple testing adjustment, two with specific externalizing and five with specific internalizing psychopathology. PRSs predicted general psychopathology independently of each other, with the exception of depression and depressive symptom PRSs. Most PRSs associated with a specific psychopathology domain, were also associated with general child psychopathology. CONCLUSIONS: The results suggest that PRSs based on current GWASs of psychiatric phenotypes tend to be associated with general psychopathology, or both general and specific psychiatric domains, but not with one specific psychopathology domain only. Furthermore, PRSs can be combined to improve predictive ability. PRS users should therefore be conscious of nonspecificity and consider using multiple PRSs simultaneously, when predicting psychiatric disorders. En ligne : http://dx.doi.org/10.1111/jcpp.13501 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=475

Cross-level analysis of molecular and neurobehavioral function in a prospective series of patients with germline heterozygous PTEN mutations with and without autism / Thomas W. FRAZIER in Molecular Autism, 12 (2021)  

Public ISBD [article]  inMolecular Autism > 12 (2021) . - 5p. Titre : Cross-level analysis of molecular and neurobehavioral function in a prospective series of patients with germline heterozygous PTEN mutations with and without autism Type de document : texte imprimé Auteurs : Thomas W. FRAZIER, Auteur ; Ritika JAINI, Auteur ; Robyn M. BUSCH, Auteur ; Matthew WOLF, Auteur ; Tammy SADLER, Auteur ; Patricia KLAAS, Auteur ; Antonio Y. HARDAN, Auteur ; Julian A. MARTINEZ-AGOSTO, Auteur ; Mustafa SAHIN, Auteur ; Charis ENG, Auteur Article en page(s) : 5p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder  Behavior  Cognition  Molecular  Pten  Protein Index. décimale : PER Périodiques Résumé : BACKGROUND: PTEN is a well-established risk gene for autism spectrum disorder (ASD). Yet, little is known about how PTEN mutations and associated molecular processes influence neurobehavioral function in mutation carriers with (PTEN-ASD) and without ASD (PTEN no-ASD). The primary aim of the present study was to examine group differences in peripheral blood-derived PTEN pathway protein levels between PTEN-ASD, PTEN no-ASD, and idiopathic macrocephalic ASD patients (macro-ASD). Secondarily, associations between protein levels and neurobehavioral functions were examined in the full cohort. METHODS: Patients were recruited at four tertiary medical centers. Peripheral blood-derived protein levels from canonical PTEN pathways (PI3K/AKT and MAPK/ERK) were analyzed using Western blot analyses blinded to genotype and ASD status. Neurobehavioral measures included standardized assessments of global cognitive ability and multiple neurobehavioral domains. Analysis of variance models examined group differences in demographic, neurobehavioral, and protein measures. Bivariate correlations, structural models, and statistical learning procedures estimated associations between molecular and neurobehavioral variables. To complement patient data, Western blots for downstream proteins were generated to evaluate canonical PTEN pathways in the PTEN-m3m4 mouse model. RESULTS: Participants included 61 patients (25 PTEN-ASD, 16 PTEN no-ASD, and 20 macro-ASD). Decreased PTEN and S6 were observed in both PTEN mutation groups. Reductions in MnSOD and increases in P-S6 were observed in ASD groups. Elevated neural P-AKT/AKT and P-S6/S6 from PTEN murine models parallel our patient observations. Patient PTEN and AKT levels were independently associated with global cognitive ability, and p27 expression was associated with frontal sub-cortical functions. As a group, molecular measures added significant predictive value to several neurobehavioral domains over and above PTEN mutation status. LIMITATIONS: Sample sizes were small, precluding within-group analyses. Protein and neurobehavioral data were limited to a single evaluation. A small number of patients were excluded with invalid protein data, and cognitively impaired patients had missing data on some assessments. CONCLUSIONS: Several canonical PTEN pathway molecules appear to influence the presence of ASD and modify neurobehavioral function in PTEN mutation patients. Protein assays of the PTEN pathway may be useful for predicting neurobehavioral outcomes in PTEN patients. Future longitudinal analyses are needed to replicate these findings and evaluate within-group relationships between protein and neurobehavioral measures. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02461446. En ligne : http://dx.doi.org/10.1186/s13229-020-00406-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=442 [article] Cross-level analysis of molecular and neurobehavioral function in a prospective series of patients with germline heterozygous PTEN mutations with and without autism [texte imprimé] / Thomas W. FRAZIER, Auteur ; Ritika JAINI, Auteur ; Robyn M. BUSCH, Auteur ; Matthew WOLF, Auteur ; Tammy SADLER, Auteur ; Patricia KLAAS, Auteur ; Antonio Y. HARDAN, Auteur ; Julian A. MARTINEZ-AGOSTO, Auteur ; Mustafa SAHIN, Auteur ; Charis ENG, Auteur . - 5p. Langues : Anglais (eng) in Molecular Autism > 12 (2021) . - 5p. Mots-clés : Autism spectrum disorder  Behavior  Cognition  Molecular  Pten  Protein Index. décimale : PER Périodiques Résumé : BACKGROUND: PTEN is a well-established risk gene for autism spectrum disorder (ASD). Yet, little is known about how PTEN mutations and associated molecular processes influence neurobehavioral function in mutation carriers with (PTEN-ASD) and without ASD (PTEN no-ASD). The primary aim of the present study was to examine group differences in peripheral blood-derived PTEN pathway protein levels between PTEN-ASD, PTEN no-ASD, and idiopathic macrocephalic ASD patients (macro-ASD). Secondarily, associations between protein levels and neurobehavioral functions were examined in the full cohort. METHODS: Patients were recruited at four tertiary medical centers. Peripheral blood-derived protein levels from canonical PTEN pathways (PI3K/AKT and MAPK/ERK) were analyzed using Western blot analyses blinded to genotype and ASD status. Neurobehavioral measures included standardized assessments of global cognitive ability and multiple neurobehavioral domains. Analysis of variance models examined group differences in demographic, neurobehavioral, and protein measures. Bivariate correlations, structural models, and statistical learning procedures estimated associations between molecular and neurobehavioral variables. To complement patient data, Western blots for downstream proteins were generated to evaluate canonical PTEN pathways in the PTEN-m3m4 mouse model. RESULTS: Participants included 61 patients (25 PTEN-ASD, 16 PTEN no-ASD, and 20 macro-ASD). Decreased PTEN and S6 were observed in both PTEN mutation groups. Reductions in MnSOD and increases in P-S6 were observed in ASD groups. Elevated neural P-AKT/AKT and P-S6/S6 from PTEN murine models parallel our patient observations. Patient PTEN and AKT levels were independently associated with global cognitive ability, and p27 expression was associated with frontal sub-cortical functions. As a group, molecular measures added significant predictive value to several neurobehavioral domains over and above PTEN mutation status. LIMITATIONS: Sample sizes were small, precluding within-group analyses. Protein and neurobehavioral data were limited to a single evaluation. A small number of patients were excluded with invalid protein data, and cognitively impaired patients had missing data on some assessments. CONCLUSIONS: Several canonical PTEN pathway molecules appear to influence the presence of ASD and modify neurobehavioral function in PTEN mutation patients. Protein assays of the PTEN pathway may be useful for predicting neurobehavioral outcomes in PTEN patients. Future longitudinal analyses are needed to replicate these findings and evaluate within-group relationships between protein and neurobehavioral measures. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02461446. En ligne : http://dx.doi.org/10.1186/s13229-020-00406-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=442

Editorial Perspective: Why is there such a mismatch between traditional heritability estimates and molecular genetic findings for behavioural traits? / Anita THAPAR in Journal of Child Psychology and Psychiatry, 55-10 (October 2014)  

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Evolution in Nervous Systems / E.A. ARBAS in Annual Review of Neuroscience, 14 (1991)

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Exploring the heterogeneity of neural social indices for genetically distinct etiologies of autism / Caitlin M. HUDAC in Journal of Neurodevelopmental Disorders, 9-1 (December 2017)  

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Gene-environment correlations in parental emotional warmth and intolerance: genome-wide analysis over two generations of the Young Finns Study / Henrik DOBEWALL in Journal of Child Psychology and Psychiatry, 60-3 (March 2019)  

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Gene-environment interplay in externalizing behavior from childhood through adulthood / Tina KRETSCHMER in Journal of Child Psychology and Psychiatry, 63-10 (October 2022)  

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