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

Patterns of Risk for Multiple Co-Occurring Medical Conditions Replicate Across Distinct Cohorts of Children with Autism Spectrum Disorder / Kimberly A. ALDINGER in Autism Research, 8-6 (December 2015)  

Public ISBD [article]  inAutism Research > 8-6 (December 2015) . - p.771-781 Titre : Patterns of Risk for Multiple Co-Occurring Medical Conditions Replicate Across Distinct Cohorts of Children with Autism Spectrum Disorder Type de document : Texte imprimé et/ou numérique Auteurs : Kimberly A. ALDINGER, Auteur ; Christianne J. LANE, Auteur ; Jeremy VEENSTRA-VANDERWEELE, Auteur ; Pat LEVITT, Auteur Article en page(s) : p.771-781 Langues : Anglais (eng) Mots-clés : gastrointestinal disturbances  sleep  seizure  medical symptoms Index. décimale : PER Périodiques Résumé : Children with autism spectrum disorder (ASD) may present with multiple medical conditions in addition to ASD symptoms. This study investigated whether there are predictive patterns of medical conditions that co-occur with ASD, which could inform medical evaluation and treatment in ASD, as well as potentially identify etiologically meaningful subgroups. Medical history data were queried in the multiplex family Autism Genetic Resource Exchange (AGRE). Fourteen medical conditions were analyzed. Replication in the Simons Simplex Collection (SSC) was attempted using available medical condition data on gastrointestinal disturbances (GID), sleep problems, allergy and epilepsy. In the AGRE cohort, no discrete clusters emerged among 14 medical conditions. GID and seizures were enriched in unaffected family members, and together with sleep problems, were represented in both AGRE and SSC. Further analysis of these medical conditions identified predictive co-occurring patterns in both samples. For a child with ASD, the presence of GID predicts sleep problems and vice versa, with an approximately 2-fold odds ratio in each direction. These risk patterns were replicated in the SSC sample, and in addition, there was increased risk for seizures and sleep problems to co-occur with GID. In these cohorts, seizure alone was not predictive of the other conditions co-occurring, but behavioral impairments were more severe as the number of co-occurring medical symptoms increased. These findings indicate that interdisciplinary clinical care for children with ASD will benefit from evaluation for specific patterns of medical conditions in the affected child and their family members. Autism Res 2015, 8: 771–781. © 015 The Authors Autism Research published by Wiley Periodicals, Inc. on behalf of International Society for Autism Research. En ligne : http://dx.doi.org/10.1002/aur.1492 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=278 [article] Patterns of Risk for Multiple Co-Occurring Medical Conditions Replicate Across Distinct Cohorts of Children with Autism Spectrum Disorder [Texte imprimé et/ou numérique] / Kimberly A. ALDINGER, Auteur ; Christianne J. LANE, Auteur ; Jeremy VEENSTRA-VANDERWEELE, Auteur ; Pat LEVITT, Auteur . - p.771-781. Langues : Anglais (eng) in Autism Research > 8-6 (December 2015) . - p.771-781 Mots-clés : gastrointestinal disturbances  sleep  seizure  medical symptoms Index. décimale : PER Périodiques Résumé : Children with autism spectrum disorder (ASD) may present with multiple medical conditions in addition to ASD symptoms. This study investigated whether there are predictive patterns of medical conditions that co-occur with ASD, which could inform medical evaluation and treatment in ASD, as well as potentially identify etiologically meaningful subgroups. Medical history data were queried in the multiplex family Autism Genetic Resource Exchange (AGRE). Fourteen medical conditions were analyzed. Replication in the Simons Simplex Collection (SSC) was attempted using available medical condition data on gastrointestinal disturbances (GID), sleep problems, allergy and epilepsy. In the AGRE cohort, no discrete clusters emerged among 14 medical conditions. GID and seizures were enriched in unaffected family members, and together with sleep problems, were represented in both AGRE and SSC. Further analysis of these medical conditions identified predictive co-occurring patterns in both samples. For a child with ASD, the presence of GID predicts sleep problems and vice versa, with an approximately 2-fold odds ratio in each direction. These risk patterns were replicated in the SSC sample, and in addition, there was increased risk for seizures and sleep problems to co-occur with GID. In these cohorts, seizure alone was not predictive of the other conditions co-occurring, but behavioral impairments were more severe as the number of co-occurring medical symptoms increased. These findings indicate that interdisciplinary clinical care for children with ASD will benefit from evaluation for specific patterns of medical conditions in the affected child and their family members. Autism Res 2015, 8: 771–781. © 015 The Authors Autism Research published by Wiley Periodicals, Inc. on behalf of International Society for Autism Research. En ligne : http://dx.doi.org/10.1002/aur.1492 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=278

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