Altered glial marker expression in autistic post-mortem prefrontal cortex and cerebellum / Catherine EDMONSON in Molecular Autism, (January 2014)  

Public ISBD [article]  inMolecular Autism > (January 2014) Titre : Altered glial marker expression in autistic post-mortem prefrontal cortex and cerebellum Type de document : texte imprimé Auteurs : Catherine EDMONSON, Auteur ; Mark ZIATS, Auteur ; Owen RENNERT, Auteur Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : The cellular mechanism(s) underlying autism spectrum disorders (ASDs) are not completely understood, but ASDs are thought to ultimately result from disrupted synaptogenesis. However, studies have also shown that glial cell numbers and function are abnormal in post-mortem brain tissue from autistic patients. Direct assessment of glial cells in post-mortem human brain tissue is technically challenging, limiting glial research in human ASD studies. Therefore, we attempted to determine if glial cell-type specific markers may be altered in autistic brain tissue in a manner that is consistent with known cellular findings, such that they could serve as a proxy for glial cell numbers and/or activation patterns. We assessed the relative expression of five glial-specific markers and two neuron-specific markers via qRT-PCR. We studied tissue samples from the prefrontal cortex (PFC) and cerebellum of nine post-mortem autistic brain samples and nine neurologically-normal controls. Relative fold-change in gene expression was determined using the DeltaDeltaCt method normalized to housekeeping gene beta-actin, with a two-tailed Student's t-test P 0.05 between groups considered as significant. Both astrocyte- and microglial-specific markers were significantly more highly expressed in autistic PFC as compared to matched controls, while in the cerebellum only astrocyte markers were elevated in autistic samples. In contrast, neuron-specific markers showed significantly lower expression in both the PFC and cerebellum of autistic patients as compared to controls. These results are in line with previous findings showing increased glial cell numbers and up-regulation of glial cell gene expression in autistic post-mortem brain tissue, particularly in the PFC, as well as decreased number of neurons in both the PFC and cerebellum of autistic patients. The concordance of these results with cell-level studies in post-mortem autistic brain tissue suggests that expression of glial cell-type specific markers may serve as a useful alternative to traditional cellular characterization methods, especially when appropriately-preserved post-mortem tissue is lacking. Additionally, these results demonstrate abnormal glial-specific gene expression in autistic brains, supporting previous studies that have observed altered glial cell numbers or activation patterns in ASDs. Future work should directly assess the correlation between cell-type specific marker levels and cell number and activation patterns. En ligne : http://dx.doi.org/10.1186/2040-2392-5-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227 [article] Altered glial marker expression in autistic post-mortem prefrontal cortex and cerebellum [texte imprimé] / Catherine EDMONSON, Auteur ; Mark ZIATS, Auteur ; Owen RENNERT, Auteur. Langues : Anglais (eng) in Molecular Autism > (January 2014) Index. décimale : PER Périodiques Résumé : The cellular mechanism(s) underlying autism spectrum disorders (ASDs) are not completely understood, but ASDs are thought to ultimately result from disrupted synaptogenesis. However, studies have also shown that glial cell numbers and function are abnormal in post-mortem brain tissue from autistic patients. Direct assessment of glial cells in post-mortem human brain tissue is technically challenging, limiting glial research in human ASD studies. Therefore, we attempted to determine if glial cell-type specific markers may be altered in autistic brain tissue in a manner that is consistent with known cellular findings, such that they could serve as a proxy for glial cell numbers and/or activation patterns. We assessed the relative expression of five glial-specific markers and two neuron-specific markers via qRT-PCR. We studied tissue samples from the prefrontal cortex (PFC) and cerebellum of nine post-mortem autistic brain samples and nine neurologically-normal controls. Relative fold-change in gene expression was determined using the DeltaDeltaCt method normalized to housekeeping gene beta-actin, with a two-tailed Student's t-test P 0.05 between groups considered as significant. Both astrocyte- and microglial-specific markers were significantly more highly expressed in autistic PFC as compared to matched controls, while in the cerebellum only astrocyte markers were elevated in autistic samples. In contrast, neuron-specific markers showed significantly lower expression in both the PFC and cerebellum of autistic patients as compared to controls. These results are in line with previous findings showing increased glial cell numbers and up-regulation of glial cell gene expression in autistic post-mortem brain tissue, particularly in the PFC, as well as decreased number of neurons in both the PFC and cerebellum of autistic patients. The concordance of these results with cell-level studies in post-mortem autistic brain tissue suggests that expression of glial cell-type specific markers may serve as a useful alternative to traditional cellular characterization methods, especially when appropriately-preserved post-mortem tissue is lacking. Additionally, these results demonstrate abnormal glial-specific gene expression in autistic brains, supporting previous studies that have observed altered glial cell numbers or activation patterns in ASDs. Future work should directly assess the correlation between cell-type specific marker levels and cell number and activation patterns. En ligne : http://dx.doi.org/10.1186/2040-2392-5-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227

Sex-biased gene expression in the developing brain: implications for autism spectrum disorders / Mark ZIATS in Molecular Autism, (May 2013)  

Public ISBD [article]  inMolecular Autism > (May 2013) . - 3 p. Titre : Sex-biased gene expression in the developing brain: implications for autism spectrum disorders Type de document : texte imprimé Auteurs : Mark ZIATS, Auteur ; Owen RENNERT, Auteur Année de publication : 2013 Article en page(s) : 3 p. Langues : Anglais (eng) Mots-clés : Autistic disorder  Gene expression  Sex differences Index. décimale : PER Périodiques Résumé : Autism spectrum disorders affect significantly more males than females. Understanding sex differences in normal human brain development may provide insight into the mechanism(s) underlying this disparity; however, studies of sex differences in brain development at the genomic level are lacking. Here, we report a re-analysis of sex-specific gene expression from a recent large transcriptomic study of normal human brain development, to determine whether sex-biased genes relate to specific mechanistic processes. We discovered that male-biased genes are enriched for the processes of extracellular matrix formation/glycoproteins, immune response, chromatin, and cell cytoskeleton. We highlight that these pathways have been repeatedly implicated in autism and demonstrate that autism candidate genes are also enriched for these pathways. We propose that the overlap of these male-specific brain transcriptional modules with the same pathways in autism spectrum disorders may partially explain the increased incidence of autism in males. En ligne : http://dx.doi.org/10.1186/2040-2392-4-10 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=202 [article] Sex-biased gene expression in the developing brain: implications for autism spectrum disorders [texte imprimé] / Mark ZIATS, Auteur ; Owen RENNERT, Auteur . - 2013 . - 3 p. Langues : Anglais (eng) in Molecular Autism > (May 2013) . - 3 p. Mots-clés : Autistic disorder  Gene expression  Sex differences Index. décimale : PER Périodiques Résumé : Autism spectrum disorders affect significantly more males than females. Understanding sex differences in normal human brain development may provide insight into the mechanism(s) underlying this disparity; however, studies of sex differences in brain development at the genomic level are lacking. Here, we report a re-analysis of sex-specific gene expression from a recent large transcriptomic study of normal human brain development, to determine whether sex-biased genes relate to specific mechanistic processes. We discovered that male-biased genes are enriched for the processes of extracellular matrix formation/glycoproteins, immune response, chromatin, and cell cytoskeleton. We highlight that these pathways have been repeatedly implicated in autism and demonstrate that autism candidate genes are also enriched for these pathways. We propose that the overlap of these male-specific brain transcriptional modules with the same pathways in autism spectrum disorders may partially explain the increased incidence of autism in males. En ligne : http://dx.doi.org/10.1186/2040-2392-4-10 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=202

A systematic variant annotation approach for ranking genes associated with autism spectrum disorders / Eric LARSEN in Molecular Autism, 7 (2016)  

Public ISBD [article]  inMolecular Autism > 7 (2016) . - 44p. Titre : A systematic variant annotation approach for ranking genes associated with autism spectrum disorders Type de document : texte imprimé Auteurs : Eric LARSEN, Auteur ; Idan MENASHE, Auteur ; Mark N. ZIATS, Auteur ; Wayne PEREANU, Auteur ; Alan PACKER, Auteur ; Sharmila BANERJEE-BASU, Auteur Article en page(s) : 44p. Langues : Anglais (eng) Mots-clés : Algorithms  Autism Spectrum Disorder/genetics/physiopathology  DNA-Binding Proteins/genetics  Databases, Genetic  Datasets as Topic  Gene Expression  Genetic Predisposition to Disease  Genetic Variation  Homeodomain Proteins/genetics  Humans  Molecular Sequence Annotation  Nerve Tissue Proteins/genetics  Research Design  Transcription Factors/genetics  Autistic disorder  Autosomal recessive  Common variants  Genetic variation  Rare variants Index. décimale : PER Périodiques Résumé : BACKGROUND: The search for genetic factors underlying autism spectrum disorders (ASD) has led to the identification of hundreds of genes containing thousands of variants that differ in mode of inheritance, effect size, frequency, and function. A major challenge involves assessing the collective evidence in an unbiased, systematic manner for their functional relevance. METHODS: Here, we describe a scoring algorithm for prioritization of candidate genes based on the cumulative strength of evidence for each ASD-associated variant cataloged in AutDB (also known as SFARI Gene). We retrieved data from 889 publications to generate a dataset of 2187 rare and 711 common variants distributed across 461 genes implicated in ASD. Each individual variant was manually annotated with multiple attributes extracted from the original report, followed by score assignment using a set of standardized parameters yielding a single score for each gene. RESULTS: There was a wide variation in scores; SHANK3, CHD8, and ADNP had distinctly higher scores than all other genes in the dataset. Our gene scores were significantly correlated with other recently published rankings of ASD genes (RSpearman = 0.40-0.63; p< 0.0001), providing support for our scoring algorithm. CONCLUSIONS: This new resource, which is freely available, for the first time aggregates on one-platform variants identified from various study types (simplex, multiplex, multigenerational, and consanguineous families), from both common and rare variants, and also incorporates their putative functional consequences to arrive at a genetically and biologically driven ranking scheme. This work represents a major step in moving from simply cataloging autism variants to using data-driven approaches to gain insight into their significance. En ligne : http://dx.doi.org/10.1186/s13229-016-0103-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=328 [article] A systematic variant annotation approach for ranking genes associated with autism spectrum disorders [texte imprimé] / Eric LARSEN, Auteur ; Idan MENASHE, Auteur ; Mark N. ZIATS, Auteur ; Wayne PEREANU, Auteur ; Alan PACKER, Auteur ; Sharmila BANERJEE-BASU, Auteur . - 44p. Langues : Anglais (eng) in Molecular Autism > 7 (2016) . - 44p. Mots-clés : Algorithms  Autism Spectrum Disorder/genetics/physiopathology  DNA-Binding Proteins/genetics  Databases, Genetic  Datasets as Topic  Gene Expression  Genetic Predisposition to Disease  Genetic Variation  Homeodomain Proteins/genetics  Humans  Molecular Sequence Annotation  Nerve Tissue Proteins/genetics  Research Design  Transcription Factors/genetics  Autistic disorder  Autosomal recessive  Common variants  Genetic variation  Rare variants Index. décimale : PER Périodiques Résumé : BACKGROUND: The search for genetic factors underlying autism spectrum disorders (ASD) has led to the identification of hundreds of genes containing thousands of variants that differ in mode of inheritance, effect size, frequency, and function. A major challenge involves assessing the collective evidence in an unbiased, systematic manner for their functional relevance. METHODS: Here, we describe a scoring algorithm for prioritization of candidate genes based on the cumulative strength of evidence for each ASD-associated variant cataloged in AutDB (also known as SFARI Gene). We retrieved data from 889 publications to generate a dataset of 2187 rare and 711 common variants distributed across 461 genes implicated in ASD. Each individual variant was manually annotated with multiple attributes extracted from the original report, followed by score assignment using a set of standardized parameters yielding a single score for each gene. RESULTS: There was a wide variation in scores; SHANK3, CHD8, and ADNP had distinctly higher scores than all other genes in the dataset. Our gene scores were significantly correlated with other recently published rankings of ASD genes (RSpearman = 0.40-0.63; p< 0.0001), providing support for our scoring algorithm. CONCLUSIONS: This new resource, which is freely available, for the first time aggregates on one-platform variants identified from various study types (simplex, multiplex, multigenerational, and consanguineous families), from both common and rare variants, and also incorporates their putative functional consequences to arrive at a genetically and biologically driven ranking scheme. This work represents a major step in moving from simply cataloging autism variants to using data-driven approaches to gain insight into their significance. En ligne : http://dx.doi.org/10.1186/s13229-016-0103-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=328

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