Association of oxytocin receptor (OXTR) gene variants with multiple phenotype domains of autism spectrum disorder / Daniel B. CAMPBELL in Journal of Neurodevelopmental Disorders, 3-2 (June 2011)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 3-2 (June 2011) . - p.101-12 Titre : Association of oxytocin receptor (OXTR) gene variants with multiple phenotype domains of autism spectrum disorder Type de document : Texte imprimé et/ou numérique Auteurs : Daniel B. CAMPBELL, Auteur ; D. DATTA, Auteur ; S. T. JONES, Auteur ; Evon BATEY LEE, Auteur ; J. S. SUTCLIFFE, Auteur ; E. A. HAMMOCK, Auteur ; P. LEVITT, Auteur Article en page(s) : p.101-12 Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Autism spectrum disorder (ASD) is characterized by core deficits in social behavior, communication, and behavioral flexibility. Several lines of evidence indicate that oxytocin, signaling through its receptor (OXTR), is important in a wide range of social behaviors. In attempts to determine whether genetic variations in the oxytocin signaling system contribute to ASD susceptibility, seven recent reports indicated association of common genetic polymorphisms in the OXTR gene with ASD. Each involved relatively small sample sizes (57 to 436 families) and, where it was examined, failed to identify association of OXTR polymorphisms with measures of social behavior in individuals with ASD. We report genetic association analysis of 25 markers spanning the OXTR locus in 1,238 pedigrees including 2,333 individuals with ASD. Association of three markers previously implicated in ASD susceptibility, rs2268493 (P = 0.043), rs1042778 (P = 0.037), and rs7632287 (P = 0.016), was observed. Further, these genetic markers were associated with multiple core ASD phenotypes, including social domain dysfunction, measured by standardized instruments used to diagnose and describe ASD. The data suggest association of OXTR genetic polymorphisms with ASD, although the results should be interpreted with caution because none of the significant associations would survive appropriate correction for multiple comparisons. However, the current findings of association in a large independent cohort are consistent with previous results, and the biological plausibility of participation of the oxytocin signaling system in modulating social disruptions characteristic of ASD, suggest that functional polymorphisms of OXTR may contribute to ASD risk in a subset of families. En ligne : http://dx.doi.org/10.1007/s11689-010-9071-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=343 [article] Association of oxytocin receptor (OXTR) gene variants with multiple phenotype domains of autism spectrum disorder [Texte imprimé et/ou numérique] / Daniel B. CAMPBELL, Auteur ; D. DATTA, Auteur ; S. T. JONES, Auteur ; Evon BATEY LEE, Auteur ; J. S. SUTCLIFFE, Auteur ; E. A. HAMMOCK, Auteur ; P. LEVITT, Auteur . - p.101-12. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 3-2 (June 2011) . - p.101-12 Index. décimale : PER Périodiques Résumé : Autism spectrum disorder (ASD) is characterized by core deficits in social behavior, communication, and behavioral flexibility. Several lines of evidence indicate that oxytocin, signaling through its receptor (OXTR), is important in a wide range of social behaviors. In attempts to determine whether genetic variations in the oxytocin signaling system contribute to ASD susceptibility, seven recent reports indicated association of common genetic polymorphisms in the OXTR gene with ASD. Each involved relatively small sample sizes (57 to 436 families) and, where it was examined, failed to identify association of OXTR polymorphisms with measures of social behavior in individuals with ASD. We report genetic association analysis of 25 markers spanning the OXTR locus in 1,238 pedigrees including 2,333 individuals with ASD. Association of three markers previously implicated in ASD susceptibility, rs2268493 (P = 0.043), rs1042778 (P = 0.037), and rs7632287 (P = 0.016), was observed. Further, these genetic markers were associated with multiple core ASD phenotypes, including social domain dysfunction, measured by standardized instruments used to diagnose and describe ASD. The data suggest association of OXTR genetic polymorphisms with ASD, although the results should be interpreted with caution because none of the significant associations would survive appropriate correction for multiple comparisons. However, the current findings of association in a large independent cohort are consistent with previous results, and the biological plausibility of participation of the oxytocin signaling system in modulating social disruptions characteristic of ASD, suggest that functional polymorphisms of OXTR may contribute to ASD risk in a subset of families. En ligne : http://dx.doi.org/10.1007/s11689-010-9071-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=343

Comparative DNA methylation among females with neurodevelopmental disorders and seizures identifies TAC1 as a MeCP2 target gene / Kimberly A. ALDINGER in Journal of Neurodevelopmental Disorders, 5-1 (December 2013)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 5-1 (December 2013) . - p.15 Titre : Comparative DNA methylation among females with neurodevelopmental disorders and seizures identifies TAC1 as a MeCP2 target gene Type de document : Texte imprimé et/ou numérique Auteurs : Kimberly A. ALDINGER, Auteur ; J. T. PLUMMER, Auteur ; P. LEVITT, Auteur Article en page(s) : p.15 Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : BACKGROUND: Several proteins involved in epigenetic regulation cause syndromic neurodevelopmental disorders when human genes are mutated. More general involvement of epigenetic mechanisms in neurodevelopmental phenotypes is unclear. METHODS: In an attempt to determine whether DNA methylation differentiates clinical subgroups, profiling was performed on bisulfite converted DNA from lymphoblastoid cell lines (LCLs) in discovery (n = 20) and replication (n = 40) cohorts of females with Rett syndrome (RTT; n = 18), autism (AUT; n = 17), seizure disorder (SEZ; n = 6), and controls (CTL; n = 19) using Illumina HumanMethylation27 arrays. TAC1 CpGs were validated using a Sequenom EpiTYPER assay and expression was measured in LCLs and postmortem brain. Chromatin immunoprecipitation was performed in HEK cells. Cells were treated with valproic acid and MeCP2 binding was assessed. RESULTS: Two female-only cohorts were analyzed. DNA methylation profiling in a discovery cohort identified 40 CpGs that exhibited statistically significant differential methylation (>/=15%) between clinical groups (P <0.01). Hierarchical clustering and principal components analysis suggested neurodevelopmental groups were distinct from CTL, but not from each other. In a larger and more heterogeneous replication cohort, these 40 CpG sites suggested no clear difference between clinical groups. Pooled analysis of DNA methylation across all 60 samples suggested only four differentially methylated CpG sites (P <0.0005), including TAC1. TAC1 promoter CpG hypermethylation was validated in AUT and SEZ (P <0.005). Analyzed for the first time in postmortem brain, TAC1 expression was reduced in cingulate cortex in RTT and AUT+SEZ (P = 0.003). However, no significant difference in TAC1 promoter CpG methylation was detected in RTT and AUT+SEZ brains. Additional molecular analyses revealed that MeCP2 binds directly to the TAC1 promoter and is sensitive to antiepileptic drug treatment. CONCLUSION: These data suggest that DNA methylation is not widely altered in RTT, consistent with subtle changes in gene expression previously observed. However, TAC1 may be an important target for further functional analyses in RTT. Studies of larger sample cohorts using primary cells that also consider shared clinical features and drug treatments may be required to address apparent subtle disruptions of DNA methylation in neurodevelopmental disorders. En ligne : http://dx.doi.org/10.1186/1866-1955-5-15 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=345 [article] Comparative DNA methylation among females with neurodevelopmental disorders and seizures identifies TAC1 as a MeCP2 target gene [Texte imprimé et/ou numérique] / Kimberly A. ALDINGER, Auteur ; J. T. PLUMMER, Auteur ; P. LEVITT, Auteur . - p.15. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 5-1 (December 2013) . - p.15 Index. décimale : PER Périodiques Résumé : BACKGROUND: Several proteins involved in epigenetic regulation cause syndromic neurodevelopmental disorders when human genes are mutated. More general involvement of epigenetic mechanisms in neurodevelopmental phenotypes is unclear. METHODS: In an attempt to determine whether DNA methylation differentiates clinical subgroups, profiling was performed on bisulfite converted DNA from lymphoblastoid cell lines (LCLs) in discovery (n = 20) and replication (n = 40) cohorts of females with Rett syndrome (RTT; n = 18), autism (AUT; n = 17), seizure disorder (SEZ; n = 6), and controls (CTL; n = 19) using Illumina HumanMethylation27 arrays. TAC1 CpGs were validated using a Sequenom EpiTYPER assay and expression was measured in LCLs and postmortem brain. Chromatin immunoprecipitation was performed in HEK cells. Cells were treated with valproic acid and MeCP2 binding was assessed. RESULTS: Two female-only cohorts were analyzed. DNA methylation profiling in a discovery cohort identified 40 CpGs that exhibited statistically significant differential methylation (>/=15%) between clinical groups (P <0.01). Hierarchical clustering and principal components analysis suggested neurodevelopmental groups were distinct from CTL, but not from each other. In a larger and more heterogeneous replication cohort, these 40 CpG sites suggested no clear difference between clinical groups. Pooled analysis of DNA methylation across all 60 samples suggested only four differentially methylated CpG sites (P <0.0005), including TAC1. TAC1 promoter CpG hypermethylation was validated in AUT and SEZ (P <0.005). Analyzed for the first time in postmortem brain, TAC1 expression was reduced in cingulate cortex in RTT and AUT+SEZ (P = 0.003). However, no significant difference in TAC1 promoter CpG methylation was detected in RTT and AUT+SEZ brains. Additional molecular analyses revealed that MeCP2 binds directly to the TAC1 promoter and is sensitive to antiepileptic drug treatment. CONCLUSION: These data suggest that DNA methylation is not widely altered in RTT, consistent with subtle changes in gene expression previously observed. However, TAC1 may be an important target for further functional analyses in RTT. Studies of larger sample cohorts using primary cells that also consider shared clinical features and drug treatments may be required to address apparent subtle disruptions of DNA methylation in neurodevelopmental disorders. En ligne : http://dx.doi.org/10.1186/1866-1955-5-15 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=345

Complete or partial reduction of the Met receptor tyrosine kinase in distinct circuits differentially impacts mouse behavior / B. L. THOMPSON in Journal of Neurodevelopmental Disorders, 7-1 (December 2015)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 7-1 (December 2015) . - p.35 Titre : Complete or partial reduction of the Met receptor tyrosine kinase in distinct circuits differentially impacts mouse behavior Type de document : Texte imprimé et/ou numérique Auteurs : B. L. THOMPSON, Auteur ; P. LEVITT, Auteur Article en page(s) : p.35 Langues : Anglais (eng) Mots-clés : Autism  Behavior  Fear learning  Gene dose  Met  Mouse  Phenotype Index. décimale : PER Périodiques Résumé : BACKGROUND: Our laboratory discovered that the gene encoding the receptor tyrosine kinase, MET, contributes to autism risk. Expression of MET is reduced in human postmortem temporal lobe in autism and Rett Syndrome. Subsequent studies revealed a role for MET in human and mouse functional and structural cortical connectivity. To further understand the contribution of Met to brain development and its impact on behavior, we generated two conditional mouse lines in which Met is deleted from select populations of central nervous system neurons. Mice were then tested to determine the consequences of disrupting Met expression. METHODS: Mating of Emx1 (cre) and Met (fx/fx) mice eliminates receptor signaling from all cells arising from the dorsal pallium. Met (fx/fx) and Nestin (cre) crosses result in receptor signaling elimination from all neural cells. Behavioral tests were performed to assess cognitive, emotional, and social impairments that are observed in multiple neurodevelopmental disorders and that are in part subserved by circuits that express Met. RESULTS: Met (fx/fx) /Emx1 (cre) null mice displayed significant hypoactivity in the activity chamber and in the T-maze despite superior performance on the rotarod. Additionally, these animals showed a deficit in spontaneous alternation. Surprisingly, Met (fx/fx; fx/+) /Nestin (cre) null and heterozygous mice exhibited deficits in contextual fear conditioning, and Met (fx/+) /Nestin (cre) heterozygous mice spent less time in the closed arms of the elevated plus maze. CONCLUSIONS: These data suggest a complex contribution of Met in the development of circuits mediating social, emotional, and cognitive behavior. The impact of disrupting developmental Met expression is dependent upon circuit-specific deletion patterns and levels of receptor activity. En ligne : http://dx.doi.org/10.1186/s11689-015-9131-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=348 [article] Complete or partial reduction of the Met receptor tyrosine kinase in distinct circuits differentially impacts mouse behavior [Texte imprimé et/ou numérique] / B. L. THOMPSON, Auteur ; P. LEVITT, Auteur . - p.35. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 7-1 (December 2015) . - p.35 Mots-clés : Autism  Behavior  Fear learning  Gene dose  Met  Mouse  Phenotype Index. décimale : PER Périodiques Résumé : BACKGROUND: Our laboratory discovered that the gene encoding the receptor tyrosine kinase, MET, contributes to autism risk. Expression of MET is reduced in human postmortem temporal lobe in autism and Rett Syndrome. Subsequent studies revealed a role for MET in human and mouse functional and structural cortical connectivity. To further understand the contribution of Met to brain development and its impact on behavior, we generated two conditional mouse lines in which Met is deleted from select populations of central nervous system neurons. Mice were then tested to determine the consequences of disrupting Met expression. METHODS: Mating of Emx1 (cre) and Met (fx/fx) mice eliminates receptor signaling from all cells arising from the dorsal pallium. Met (fx/fx) and Nestin (cre) crosses result in receptor signaling elimination from all neural cells. Behavioral tests were performed to assess cognitive, emotional, and social impairments that are observed in multiple neurodevelopmental disorders and that are in part subserved by circuits that express Met. RESULTS: Met (fx/fx) /Emx1 (cre) null mice displayed significant hypoactivity in the activity chamber and in the T-maze despite superior performance on the rotarod. Additionally, these animals showed a deficit in spontaneous alternation. Surprisingly, Met (fx/fx; fx/+) /Nestin (cre) null and heterozygous mice exhibited deficits in contextual fear conditioning, and Met (fx/+) /Nestin (cre) heterozygous mice spent less time in the closed arms of the elevated plus maze. CONCLUSIONS: These data suggest a complex contribution of Met in the development of circuits mediating social, emotional, and cognitive behavior. The impact of disrupting developmental Met expression is dependent upon circuit-specific deletion patterns and levels of receptor activity. En ligne : http://dx.doi.org/10.1186/s11689-015-9131-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=348

Gaps in Current Autism Research: The Thoughts of the Autism Research Editorial Board and Associate Editors / David G. AMARAL in Autism Research, 12-5 (May 2019)  

Public ISBD [article]  inAutism Research > 12-5 (May 2019) . - p.700-714 Titre : Gaps in Current Autism Research: The Thoughts of the Autism Research Editorial Board and Associate Editors Type de document : Texte imprimé et/ou numérique Auteurs : David G. AMARAL, Auteur ; George M. ANDERSON, Auteur ; A. BAILEY, Auteur ; Raphael BERNIER, Auteur ; Somer L. BISHOP, Auteur ; Gene J. BLATT, Auteur ; Ricardo CANAL-BEDIA, Auteur ; Tony CHARMAN, Auteur ; G. DAWSON, Auteur ; P. J. DE VRIES, Auteur ; Emanuel DICICCO-BLOOM, Auteur ; Cheryl DISSANAYAKE, Auteur ; Y. KAMIO, Auteur ; R. KANA, Auteur ; N. Z. KHAN, Auteur ; A. KNOLL, Auteur ; F. KOOY, Auteur ; J. LAINHART, Auteur ; P. LEVITT, Auteur ; K. LOVELAND, Auteur ; N. MINSHEW, Auteur ; R. A. MUELLER, Auteur ; D. MURPHY, Auteur ; Peter C. MUNDY, Auteur ; S. PALENCIA, Auteur ; J. PINTO-MARTIN, Auteur ; A. RATTAZZI, Auteur ; S. ROGERS, Auteur ; W. L. STONE, Auteur ; S. J. WEBB, Auteur ; Andrew J. O. WHITEHOUSE, Auteur Article en page(s) : p.700-714 Langues : Anglais (eng) Index. décimale : PER Périodiques En ligne : http://dx.doi.org/10.1002/aur.2101 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=397 [article] Gaps in Current Autism Research: The Thoughts of the Autism Research Editorial Board and Associate Editors [Texte imprimé et/ou numérique] / David G. AMARAL, Auteur ; George M. ANDERSON, Auteur ; A. BAILEY, Auteur ; Raphael BERNIER, Auteur ; Somer L. BISHOP, Auteur ; Gene J. BLATT, Auteur ; Ricardo CANAL-BEDIA, Auteur ; Tony CHARMAN, Auteur ; G. DAWSON, Auteur ; P. J. DE VRIES, Auteur ; Emanuel DICICCO-BLOOM, Auteur ; Cheryl DISSANAYAKE, Auteur ; Y. KAMIO, Auteur ; R. KANA, Auteur ; N. Z. KHAN, Auteur ; A. KNOLL, Auteur ; F. KOOY, Auteur ; J. LAINHART, Auteur ; P. LEVITT, Auteur ; K. LOVELAND, Auteur ; N. MINSHEW, Auteur ; R. A. MUELLER, Auteur ; D. MURPHY, Auteur ; Peter C. MUNDY, Auteur ; S. PALENCIA, Auteur ; J. PINTO-MARTIN, Auteur ; A. RATTAZZI, Auteur ; S. ROGERS, Auteur ; W. L. STONE, Auteur ; S. J. WEBB, Auteur ; Andrew J. O. WHITEHOUSE, Auteur . - p.700-714. Langues : Anglais (eng) in Autism Research > 12-5 (May 2019) . - p.700-714 Index. décimale : PER Périodiques En ligne : http://dx.doi.org/10.1002/aur.2101 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=397

A new synaptic player leading to autism risk: Met receptor tyrosine kinase / M. C. JUDSON in Journal of Neurodevelopmental Disorders, 3-3 (September 2011)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 3-3 (September 2011) . - p.282-92 Titre : A new synaptic player leading to autism risk: Met receptor tyrosine kinase Type de document : Texte imprimé et/ou numérique Auteurs : M. C. JUDSON, Auteur ; K. L. EAGLESON, Auteur ; P. LEVITT, Auteur Article en page(s) : p.282-92 Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : The validity for assigning disorder risk to an autism spectrum disorder (ASD) candidate gene comes from convergent genetic, clinical, and developmental neurobiology data. Here, we review these lines of evidence from multiple human genetic studies, and non-human primate and mouse experiments that support the conclusion that the MET receptor tyrosine kinase (RTK) functions to influence synapse development in circuits relevant to certain core behavioral domains of ASD. There is association of both common functional alleles and rare copy number variants that impact levels of MET expression in the human cortex. The timing of Met expression is linked to axon terminal outgrowth and synaptogenesis in the developing rodent and primate forebrain, and both in vitro and in vivo studies implicate this RTK in dendritic branching, spine maturation, and excitatory connectivity in the neocortex. This impact can occur in a cell-nonautonomous fashion, emphasizing the unique role that Met plays in specific circuits relevant to ASD. En ligne : http://dx.doi.org/10.1007/s11689-011-9081-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=343 [article] A new synaptic player leading to autism risk: Met receptor tyrosine kinase [Texte imprimé et/ou numérique] / M. C. JUDSON, Auteur ; K. L. EAGLESON, Auteur ; P. LEVITT, Auteur . - p.282-92. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 3-3 (September 2011) . - p.282-92 Index. décimale : PER Périodiques Résumé : The validity for assigning disorder risk to an autism spectrum disorder (ASD) candidate gene comes from convergent genetic, clinical, and developmental neurobiology data. Here, we review these lines of evidence from multiple human genetic studies, and non-human primate and mouse experiments that support the conclusion that the MET receptor tyrosine kinase (RTK) functions to influence synapse development in circuits relevant to certain core behavioral domains of ASD. There is association of both common functional alleles and rare copy number variants that impact levels of MET expression in the human cortex. The timing of Met expression is linked to axon terminal outgrowth and synaptogenesis in the developing rodent and primate forebrain, and both in vitro and in vivo studies implicate this RTK in dendritic branching, spine maturation, and excitatory connectivity in the neocortex. This impact can occur in a cell-nonautonomous fashion, emphasizing the unique role that Met plays in specific circuits relevant to ASD. En ligne : http://dx.doi.org/10.1007/s11689-011-9081-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=343

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