Cytoplasm-predominant Pten associates with increased region-specific brain tyrosine hydroxylase and dopamine D2 receptors in mouse model with autistic traits / Xin HE in Molecular Autism, (November 2015)  

Public ISBD [article]  inMolecular Autism > (November 2015) . - p.1-10 Titre : Cytoplasm-predominant Pten associates with increased region-specific brain tyrosine hydroxylase and dopamine D2 receptors in mouse model with autistic traits Type de document : Texte imprimé et/ou numérique Auteurs : Xin HE, Auteur ; Stetson THACKER, Auteur ; Todd ROMIGH, Auteur ; Qi YU, Auteur ; Thomas W. FRAZIER, Auteur ; Charis ENG, Auteur Article en page(s) : p.1-10 Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders characterized by impairment in social communication/interaction and inflexible/repetitive behavior. Several lines of evidence support genetic factors as a predominant cause of ASD. Among those autism susceptibility genes that have been identified, the PTEN tumor suppressor gene, initially identified as predisposing to Cowden heritable cancer syndrome, was found to be mutated in a subset of ASD patients with extreme macrocephaly. However, the ASD-relevant molecular mechanism mediating the effect of PTEN mutations remains elusive. En ligne : http://dx.doi.org/10.1186/s13229-015-0056-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=277 [article] Cytoplasm-predominant Pten associates with increased region-specific brain tyrosine hydroxylase and dopamine D2 receptors in mouse model with autistic traits [Texte imprimé et/ou numérique] / Xin HE, Auteur ; Stetson THACKER, Auteur ; Todd ROMIGH, Auteur ; Qi YU, Auteur ; Thomas W. FRAZIER, Auteur ; Charis ENG, Auteur . - p.1-10. Langues : Anglais (eng) in Molecular Autism > (November 2015) . - p.1-10 Index. décimale : PER Périodiques Résumé : Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders characterized by impairment in social communication/interaction and inflexible/repetitive behavior. Several lines of evidence support genetic factors as a predominant cause of ASD. Among those autism susceptibility genes that have been identified, the PTEN tumor suppressor gene, initially identified as predisposing to Cowden heritable cancer syndrome, was found to be mutated in a subset of ASD patients with extreme macrocephaly. However, the ASD-relevant molecular mechanism mediating the effect of PTEN mutations remains elusive. En ligne : http://dx.doi.org/10.1186/s13229-015-0056-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=277

Decreased nuclear Pten in neural stem cells contributes to deficits in neuronal maturation / Shin Chung KANG in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 43 p. Titre : Decreased nuclear Pten in neural stem cells contributes to deficits in neuronal maturation Type de document : Texte imprimé et/ou numérique Auteurs : Shin Chung KANG, Auteur ; Ritika JAINI, Auteur ; Masahiro HITOMI, Auteur ; Hyunpil LEE, Auteur ; Nick SARN, Auteur ; Stetson THACKER, Auteur ; Charis ENG, Auteur Article en page(s) : 43 p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder  Creb activation  Neural development  Neural stem cells  Neuronal maturation  PTEN mutation Index. décimale : PER Périodiques Résumé : BACKGROUND: PTEN, a syndromic autism spectrum disorder (ASD) risk gene, is mutated in approximately 10% of macrocephalic ASD cases. Despite the described genetic association between PTEN and ASD and ensuing studies, we continue to have a limited understanding of how PTEN disruption drives ASD pathogenesis and maintenance. METHODS: We derived neural stem cells (NSCs) from the dentate gyrus (DG) of Pten(m3m4) mice, a model that recapitulates PTEN-ASD phenotypes. We subsequently characterized the expression of stemness factors, proliferation, and differentiation of neurons and glia in Pten(m3m4) NSCs using immunofluorescent and immunoblotting approaches. We also measured Creb phosphorylation by Western blot analysis and expression of Creb-regulated genes with qRT-PCR. RESULTS: The m3m4 mutation decreases Pten localization to the nucleus and its global expression over time. Pten(m3m4) NSCs exhibit persistent stemness characteristics associated with increased proliferation and a resistance to neuronal maturation during differentiation. Given the increased proliferation of Pten(m3m4) NSCs, a significant increase in the population of immature neurons relative to mature neurons occurs, an approximately tenfold decrease in the ratio between the homozygous mutant and wildtype. There is an opposite pattern of differentiation in some Pten(m3m4) glia, specifically an increase in astrocytes. These aberrant differentiation patterns associate with changes in Creb activation in Pten(m3m4/m3m4) NSCs. We specifically observed loss of Creb phosphorylation at S133 in Pten(m3m4/m3m4) NSCs and a subsequent decrease in expression of Creb-regulated genes important to neuronal function (i.e., Bdnf). Interestingly, Bdnf treatment is able to partially rescue the stunted neuronal maturation phenotype in Pten(m3m4/m3m4) NSCs. CONCLUSIONS: Constitutional disruption of Pten nuclear localization with subsequent global decrease in Pten expression generates abnormal patterns of differentiation, a stunting of neuronal maturation. The propensity of Pten disruption to restrain neurons to a more progenitor-like state may be an important feature contributing to PTEN-ASD pathogenesis. En ligne : http://dx.doi.org/10.1186/s13229-020-00337-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 [article] Decreased nuclear Pten in neural stem cells contributes to deficits in neuronal maturation [Texte imprimé et/ou numérique] / Shin Chung KANG, Auteur ; Ritika JAINI, Auteur ; Masahiro HITOMI, Auteur ; Hyunpil LEE, Auteur ; Nick SARN, Auteur ; Stetson THACKER, Auteur ; Charis ENG, Auteur . - 43 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 43 p. Mots-clés : Autism spectrum disorder  Creb activation  Neural development  Neural stem cells  Neuronal maturation  PTEN mutation Index. décimale : PER Périodiques Résumé : BACKGROUND: PTEN, a syndromic autism spectrum disorder (ASD) risk gene, is mutated in approximately 10% of macrocephalic ASD cases. Despite the described genetic association between PTEN and ASD and ensuing studies, we continue to have a limited understanding of how PTEN disruption drives ASD pathogenesis and maintenance. METHODS: We derived neural stem cells (NSCs) from the dentate gyrus (DG) of Pten(m3m4) mice, a model that recapitulates PTEN-ASD phenotypes. We subsequently characterized the expression of stemness factors, proliferation, and differentiation of neurons and glia in Pten(m3m4) NSCs using immunofluorescent and immunoblotting approaches. We also measured Creb phosphorylation by Western blot analysis and expression of Creb-regulated genes with qRT-PCR. RESULTS: The m3m4 mutation decreases Pten localization to the nucleus and its global expression over time. Pten(m3m4) NSCs exhibit persistent stemness characteristics associated with increased proliferation and a resistance to neuronal maturation during differentiation. Given the increased proliferation of Pten(m3m4) NSCs, a significant increase in the population of immature neurons relative to mature neurons occurs, an approximately tenfold decrease in the ratio between the homozygous mutant and wildtype. There is an opposite pattern of differentiation in some Pten(m3m4) glia, specifically an increase in astrocytes. These aberrant differentiation patterns associate with changes in Creb activation in Pten(m3m4/m3m4) NSCs. We specifically observed loss of Creb phosphorylation at S133 in Pten(m3m4/m3m4) NSCs and a subsequent decrease in expression of Creb-regulated genes important to neuronal function (i.e., Bdnf). Interestingly, Bdnf treatment is able to partially rescue the stunted neuronal maturation phenotype in Pten(m3m4/m3m4) NSCs. CONCLUSIONS: Constitutional disruption of Pten nuclear localization with subsequent global decrease in Pten expression generates abnormal patterns of differentiation, a stunting of neuronal maturation. The propensity of Pten disruption to restrain neurons to a more progenitor-like state may be an important feature contributing to PTEN-ASD pathogenesis. En ligne : http://dx.doi.org/10.1186/s13229-020-00337-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427

Demographic and clinical correlates of autism symptom domains and autism spectrum diagnosis / Thomas W. FRAZIER in Autism, 18-5 (July 2014)  

Public ISBD [article]  inAutism > 18-5 (July 2014) . - p.571-582 Titre : Demographic and clinical correlates of autism symptom domains and autism spectrum diagnosis Type de document : Texte imprimé et/ou numérique Auteurs : Thomas W. FRAZIER, Auteur ; Eric A. YOUNGSTROM, Auteur ; Rebecca EMBACHER, Auteur ; Antonio Y. HARDAN, Auteur ; John N. CONSTANTINO, Auteur ; Paul LAW, Auteur ; Robert L. FINDLING, Auteur ; Charis ENG, Auteur Article en page(s) : p.571-582 Langues : Anglais (eng) Mots-clés : autism spectrum disorder  autism symptoms  diagnosis  prediction Index. décimale : PER Périodiques Résumé : Demographic and clinical factors may influence assessment of autism symptoms. This study evaluated these correlates and also examined whether social communication and interaction and restricted/repetitive behavior provided unique prediction of autism spectrum disorder diagnosis. We analyzed data from 7352 siblings included in the Interactive Autism Network registry. Social communication and interaction and restricted/repetitive behavior symptoms were obtained using caregiver-reports on the Social Responsiveness Scale. Demographic and clinical correlates were covariates in regression models predicting social communication and interaction and restricted/repetitive behavior symptoms. Logistic regression and receiver operating characteristic curve analyses evaluated the incremental validity of social communication and interaction and restricted/repetitive behavior domains over and above global autism symptoms. Autism spectrum disorder diagnosis was the strongest correlate of caregiver-reported social communication and interaction and restricted/repetitive behavior symptoms. The presence of comorbid diagnoses also increased symptom levels. Social communication and interaction and restricted/repetitive behavior symptoms provided significant, but modest, incremental validity in predicting diagnosis beyond global autism symptoms. These findings suggest that autism spectrum disorder diagnosis is by far the largest determinant of quantitatively measured autism symptoms. Externalizing (attention deficit hyperactivity disorder) and internalizing (anxiety) behavior, low cognitive ability, and demographic factors may confound caregiver-report of autism symptoms, potentially necessitating a continuous norming approach to the revision of symptom measures. Social communication and interaction and restricted/repetitive behavior symptoms may provide incremental validity in the diagnosis of autism spectrum disorder. En ligne : http://dx.doi.org/10.1177/1362361313481506 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=233 [article] Demographic and clinical correlates of autism symptom domains and autism spectrum diagnosis [Texte imprimé et/ou numérique] / Thomas W. FRAZIER, Auteur ; Eric A. YOUNGSTROM, Auteur ; Rebecca EMBACHER, Auteur ; Antonio Y. HARDAN, Auteur ; John N. CONSTANTINO, Auteur ; Paul LAW, Auteur ; Robert L. FINDLING, Auteur ; Charis ENG, Auteur . - p.571-582. Langues : Anglais (eng) in Autism > 18-5 (July 2014) . - p.571-582 Mots-clés : autism spectrum disorder  autism symptoms  diagnosis  prediction Index. décimale : PER Périodiques Résumé : Demographic and clinical factors may influence assessment of autism symptoms. This study evaluated these correlates and also examined whether social communication and interaction and restricted/repetitive behavior provided unique prediction of autism spectrum disorder diagnosis. We analyzed data from 7352 siblings included in the Interactive Autism Network registry. Social communication and interaction and restricted/repetitive behavior symptoms were obtained using caregiver-reports on the Social Responsiveness Scale. Demographic and clinical correlates were covariates in regression models predicting social communication and interaction and restricted/repetitive behavior symptoms. Logistic regression and receiver operating characteristic curve analyses evaluated the incremental validity of social communication and interaction and restricted/repetitive behavior domains over and above global autism symptoms. Autism spectrum disorder diagnosis was the strongest correlate of caregiver-reported social communication and interaction and restricted/repetitive behavior symptoms. The presence of comorbid diagnoses also increased symptom levels. Social communication and interaction and restricted/repetitive behavior symptoms provided significant, but modest, incremental validity in predicting diagnosis beyond global autism symptoms. These findings suggest that autism spectrum disorder diagnosis is by far the largest determinant of quantitatively measured autism symptoms. Externalizing (attention deficit hyperactivity disorder) and internalizing (anxiety) behavior, low cognitive ability, and demographic factors may confound caregiver-report of autism symptoms, potentially necessitating a continuous norming approach to the revision of symptom measures. Social communication and interaction and restricted/repetitive behavior symptoms may provide incremental validity in the diagnosis of autism spectrum disorder. En ligne : http://dx.doi.org/10.1177/1362361313481506 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=233

Quantitative autism symptom patterns recapitulate differential mechanisms of genetic transmission in single and multiple incidence families / Thomas W. FRAZIER in Molecular Autism, (October 2015)  

Public ISBD [article]  inMolecular Autism > (October 2015) . - p.1-12 Titre : Quantitative autism symptom patterns recapitulate differential mechanisms of genetic transmission in single and multiple incidence families Type de document : Texte imprimé et/ou numérique Auteurs : Thomas W. FRAZIER, Auteur ; Eric A. YOUNGSTROM, Auteur ; Antonio Y. HARDAN, Auteur ; Stelios GEORGIADES, Auteur ; John N. CONSTANTINO, Auteur ; Charis ENG, Auteur Article en page(s) : p.1-12 Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Previous studies have demonstrated aggregation of autistic traits in undiagnosed family members of children with autism spectrum disorder (ASD), which has significant implications for ASD risk in their offspring. This study capitalizes upon a large, quantitatively characterized clinical-epidemiologic family sample to establish the extent to which family transmission pattern and sex modulate ASD trait aggregation. En ligne : http://dx.doi.org/10.1186/s13229-015-0050-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=277 [article] Quantitative autism symptom patterns recapitulate differential mechanisms of genetic transmission in single and multiple incidence families [Texte imprimé et/ou numérique] / Thomas W. FRAZIER, Auteur ; Eric A. YOUNGSTROM, Auteur ; Antonio Y. HARDAN, Auteur ; Stelios GEORGIADES, Auteur ; John N. CONSTANTINO, Auteur ; Charis ENG, Auteur . - p.1-12. Langues : Anglais (eng) in Molecular Autism > (October 2015) . - p.1-12 Index. décimale : PER Périodiques Résumé : Previous studies have demonstrated aggregation of autistic traits in undiagnosed family members of children with autism spectrum disorder (ASD), which has significant implications for ASD risk in their offspring. This study capitalizes upon a large, quantitatively characterized clinical-epidemiologic family sample to establish the extent to which family transmission pattern and sex modulate ASD trait aggregation. En ligne : http://dx.doi.org/10.1186/s13229-015-0050-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=277

Remote monitoring of social attention in neurogenetic syndromes and idiopathic neurodevelopmental disability / Thomas W. FRAZIER ; Robyn M. BUSCH ; Patricia KLAAS ; Katherine Lachlan ; Shafali JESTE ; Alexander KOLEVZON ; Eva LOTH ; Jacqueline Harris ; Tom Pepper ; Kristin Anthony ; J. Michael Graglia ; Kathryn Helde ; Christal Delagrammatikas ; Sandra Bedrosian-Sermone ; Constance Smith-Hicks ; Mustafa SAHIN ; Eric A. YOUNGSTROM ; Charis ENG ; Lacey CHETCUTI ; Antonio Y. HARDAN ; Mirko ULJAREVIC in Autism Research, 18-2 (February 2025)  

Public ISBD [article]  inAutism Research > 18-2 (February 2025) . - p.334-348 Titre : Remote monitoring of social attention in neurogenetic syndromes and idiopathic neurodevelopmental disability : Autism Research Type de document : Texte imprimé et/ou numérique Auteurs : Thomas W. FRAZIER, Auteur ; Robyn M. BUSCH, Auteur ; Patricia KLAAS, Auteur ; Katherine Lachlan, Auteur ; Shafali JESTE, Auteur ; Alexander KOLEVZON, Auteur ; Eva LOTH, Auteur ; Jacqueline Harris, Auteur ; Tom Pepper, Auteur ; Kristin Anthony, Auteur ; J. Michael Graglia, Auteur ; Kathryn Helde, Auteur ; Christal Delagrammatikas, Auteur ; Sandra Bedrosian-Sermone, Auteur ; Constance Smith-Hicks, Auteur ; Mustafa SAHIN, Auteur ; Eric A. YOUNGSTROM, Auteur ; Charis ENG, Auteur ; Lacey CHETCUTI, Auteur ; Antonio Y. HARDAN, Auteur ; Mirko ULJAREVIC, Auteur Article en page(s) : p.334-348 Langues : Anglais (eng) Mots-clés : autism spectrum disorder online reliability remote monitoring social attention validity Index. décimale : PER Périodiques Résumé : Abstract Social attention is a key aspect of neurodevelopment and is significantly altered in neurodevelopmental genetic syndromes and many individuals with idiopathic autism spectrum disorder (ASD). The primary aim of the present study was to examine the psychometric properties of webcam-collected social attention measurements, including four new specific aspects of social attention, in three genetic syndromes (PTEN Hamartoma Tumor Syndrome?PHTS; Malan Syndrome?NFIX; and SYNGAP1-related disorder?SYNGAP1), a mixed group of other neurodevelopmental genetic syndromes (Other NDGS), and individuals with a range of idiopathic neurodevelopmental disorder (NDD). The secondary aim was to evaluate the construct validity of these social attention measurements, including evaluating known-groups validity across study groups and concurrent validity for separating ASD and non-ASD cases. Participants (N?=?467, age 3?45; PHTS n?=?102, NFIX n?=?23, SYNGAP1 n?=?42, other NDGS n?=?63, idiopathic NDD n?=?53, neurotypical siblings n?=?71, and unrelated neurotypical controls n?=?113) completed a 4-min online-administered social attention paradigm that includes a variety of distinct stimuli at three timepoints (baseline, 1-month, and 4-month follow-up). Social attention measures had good scale and test?retest reliability, with the exception of measures of non-social preference and face-specific processing. Unique patterns of social attention emerged across study groups, with near neurotypical levels in PHTS and weaker social attention in NFIX and SYNGAP1 relative to controls. Global social attention had good accuracy in detecting ASD within NDGS participants. Remote monitoring social attention, including distinct aspects of social attention, may be useful for characterizing phenotypic profiles and tracking the natural history of distinct NDGS and idiopathic NDD as well as identifying ASD within NDGS. Given their reproducibility and stability, global social attention and several distinct social attention measures may be useful outcomes for future clinical trials. En ligne : https://doi.org/10.1002/aur.3290 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=547 [article] Remote monitoring of social attention in neurogenetic syndromes and idiopathic neurodevelopmental disability : Autism Research [Texte imprimé et/ou numérique] / Thomas W. FRAZIER, Auteur ; Robyn M. BUSCH, Auteur ; Patricia KLAAS, Auteur ; Katherine Lachlan, Auteur ; Shafali JESTE, Auteur ; Alexander KOLEVZON, Auteur ; Eva LOTH, Auteur ; Jacqueline Harris, Auteur ; Tom Pepper, Auteur ; Kristin Anthony, Auteur ; J. Michael Graglia, Auteur ; Kathryn Helde, Auteur ; Christal Delagrammatikas, Auteur ; Sandra Bedrosian-Sermone, Auteur ; Constance Smith-Hicks, Auteur ; Mustafa SAHIN, Auteur ; Eric A. YOUNGSTROM, Auteur ; Charis ENG, Auteur ; Lacey CHETCUTI, Auteur ; Antonio Y. HARDAN, Auteur ; Mirko ULJAREVIC, Auteur . - p.334-348. Langues : Anglais (eng) in Autism Research > 18-2 (February 2025) . - p.334-348 Mots-clés : autism spectrum disorder online reliability remote monitoring social attention validity Index. décimale : PER Périodiques Résumé : Abstract Social attention is a key aspect of neurodevelopment and is significantly altered in neurodevelopmental genetic syndromes and many individuals with idiopathic autism spectrum disorder (ASD). The primary aim of the present study was to examine the psychometric properties of webcam-collected social attention measurements, including four new specific aspects of social attention, in three genetic syndromes (PTEN Hamartoma Tumor Syndrome?PHTS; Malan Syndrome?NFIX; and SYNGAP1-related disorder?SYNGAP1), a mixed group of other neurodevelopmental genetic syndromes (Other NDGS), and individuals with a range of idiopathic neurodevelopmental disorder (NDD). The secondary aim was to evaluate the construct validity of these social attention measurements, including evaluating known-groups validity across study groups and concurrent validity for separating ASD and non-ASD cases. Participants (N?=?467, age 3?45; PHTS n?=?102, NFIX n?=?23, SYNGAP1 n?=?42, other NDGS n?=?63, idiopathic NDD n?=?53, neurotypical siblings n?=?71, and unrelated neurotypical controls n?=?113) completed a 4-min online-administered social attention paradigm that includes a variety of distinct stimuli at three timepoints (baseline, 1-month, and 4-month follow-up). Social attention measures had good scale and test?retest reliability, with the exception of measures of non-social preference and face-specific processing. Unique patterns of social attention emerged across study groups, with near neurotypical levels in PHTS and weaker social attention in NFIX and SYNGAP1 relative to controls. Global social attention had good accuracy in detecting ASD within NDGS participants. Remote monitoring social attention, including distinct aspects of social attention, may be useful for characterizing phenotypic profiles and tracking the natural history of distinct NDGS and idiopathic NDD as well as identifying ASD within NDGS. Given their reproducibility and stability, global social attention and several distinct social attention measures may be useful outcomes for future clinical trials. En ligne : https://doi.org/10.1002/aur.3290 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=547

A Twin Study of Heritable and Shared Environmental Contributions to Autism / Thomas W. FRAZIER in Journal of Autism and Developmental Disorders, 44-8 (August 2014)  

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