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Genetic modifications associated with ketogenic diet treatment in the BTBRT+Tf/J mouse model of autism spectrum disorder / Richelle MYCHASIUK in Autism Research, 10-3 (March 2017)
[article]
Titre : Genetic modifications associated with ketogenic diet treatment in the BTBRT+Tf/J mouse model of autism spectrum disorder Type de document : Texte imprimé et/ou numérique Auteurs : Richelle MYCHASIUK, Auteur ; Jong M. RHO, Auteur Article en page(s) : p.456-471 Langues : Anglais (eng) Mots-clés : autism spectrum disorder ketogenic diet RNAseq temporal cortex hippocampus mitochondria development Index. décimale : PER Périodiques Résumé : Background: Autism spectrum disorder (ASD) is a prevalent and heterogeneous neurodevelopmental disorder characterized by hallmark behavioral features. The spectrum of disorders that fall within the ASD umbrella encompass a distinct but overlapping symptom complex that likely results from an array of molecular and genetic aberrations rather than a single genetic mutation. The ketogenic diet (KD) is a high-fat low-carbohydrate anti-seizure and neuroprotective diet that has demonstrated efficacy in the treatment of ASD-like behaviors in animal and human studies. Methods: We investigated changes in mRNA and gene expression in the BTBR mouse model of ASD that may contribute to the behavioral phenotype. In addition, we sought to examine changes in gene expression following KD treatment in BTBR mice. Results: Despite significant behavioral abnormalities, expression changes in BTBR mice did not differ substantially from controls; only 33 genes were differentially expressed in the temporal cortex, and 48 in the hippocampus. Examination of these differentially expressed genes suggested deficits in the stress response and in neuronal signaling/communication. After treatment with the KD, both brain regions demonstrated improvements in ASD deficits associated with myelin formation and white matter development. Conclusions: Although our study supports many of the previously known impairments associated with ASD, such as excessive myelin formation and impaired GABAergic transmission, the RNAseq data and pathway analysis utilized here identified new therapeutic targets for analysis, such as Vitamin D pathways and cAMP signaling. En ligne : http://dx.doi.org/10.1002/aur.1682 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=304
in Autism Research > 10-3 (March 2017) . - p.456-471[article] Genetic modifications associated with ketogenic diet treatment in the BTBRT+Tf/J mouse model of autism spectrum disorder [Texte imprimé et/ou numérique] / Richelle MYCHASIUK, Auteur ; Jong M. RHO, Auteur . - p.456-471.
Langues : Anglais (eng)
in Autism Research > 10-3 (March 2017) . - p.456-471
Mots-clés : autism spectrum disorder ketogenic diet RNAseq temporal cortex hippocampus mitochondria development Index. décimale : PER Périodiques Résumé : Background: Autism spectrum disorder (ASD) is a prevalent and heterogeneous neurodevelopmental disorder characterized by hallmark behavioral features. The spectrum of disorders that fall within the ASD umbrella encompass a distinct but overlapping symptom complex that likely results from an array of molecular and genetic aberrations rather than a single genetic mutation. The ketogenic diet (KD) is a high-fat low-carbohydrate anti-seizure and neuroprotective diet that has demonstrated efficacy in the treatment of ASD-like behaviors in animal and human studies. Methods: We investigated changes in mRNA and gene expression in the BTBR mouse model of ASD that may contribute to the behavioral phenotype. In addition, we sought to examine changes in gene expression following KD treatment in BTBR mice. Results: Despite significant behavioral abnormalities, expression changes in BTBR mice did not differ substantially from controls; only 33 genes were differentially expressed in the temporal cortex, and 48 in the hippocampus. Examination of these differentially expressed genes suggested deficits in the stress response and in neuronal signaling/communication. After treatment with the KD, both brain regions demonstrated improvements in ASD deficits associated with myelin formation and white matter development. Conclusions: Although our study supports many of the previously known impairments associated with ASD, such as excessive myelin formation and impaired GABAergic transmission, the RNAseq data and pathway analysis utilized here identified new therapeutic targets for analysis, such as Vitamin D pathways and cAMP signaling. En ligne : http://dx.doi.org/10.1002/aur.1682 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=304 Mutations in RAB39B in individuals with intellectual disability, autism spectrum disorder, and macrocephaly / M. WOODBURY-SMITH in Molecular Autism, 8 (2017)
[article]
Titre : Mutations in RAB39B in individuals with intellectual disability, autism spectrum disorder, and macrocephaly Type de document : Texte imprimé et/ou numérique Auteurs : M. WOODBURY-SMITH, Auteur ; E. DENEAULT, Auteur ; R. K. C. YUEN, Auteur ; S. WALKER, Auteur ; M. ZARREI, Auteur ; G. PELLECCHIA, Auteur ; J. L. HOWE, Auteur ; N. HOANG, Auteur ; M. UDDIN, Auteur ; C. R. MARSHALL, Auteur ; C. CHRYSLER, Auteur ; A. THOMPSON, Auteur ; P. SZATMARI, Auteur ; Stephen SCHERER, Auteur Article en page(s) : 59p. Langues : Anglais (eng) Mots-clés : Intellectual disability (ID) Rab39b RNAseq Whole genome sequencing (WGS) Index. décimale : PER Périodiques Résumé : Background: Autism spectrum disorder (ASD), a developmental disorder of early childhood onset, affects males four times more frequently than females, suggesting a role for the sex chromosomes. In this study, we describe a family with ASD in which a predicted pathogenic nonsense mutation in the X-chromosome gene RAB39B segregates with ASD phenotype. Methods: Clinical phenotyping, microarray, and whole genome sequencing (WGS) were performed on the five members of this family. Maternal and female sibling X inactivation ratio was calculated, and phase was investigated. Mutant-induced pluripotent stem cells engineered for an exon 2 nonsense mutation were generated and differentiated into cortical neurons for expression and pathway analyses. Results: Two males with an inherited RAB39B mutation both presented with macrocephaly, intellectual disability (ID), and ASD. Their female sibling with the same mutation presented with ID and a broad autism phenotype. In contrast, their transmitting mother has no neurodevelopmental diagnosis. Our investigation of phase indicated maternal preferential inactivation of the mutated allele, with no such bias observed in the female sibling. We offer the explanation that this bias in X inactivation may explain the absence of a neurocognitive phenotype in the mother. Our cellular knockout model of RAB39B revealed an impact on expression in differentiated neurons for several genes implicated in brain development and function, supported by our pathway enrichment analysis. Conclusions: Penetrance for ASD is high among males but more variable among females with RAB39B mutations. A critical role for this gene in brain development and function is demonstrated. En ligne : http://dx.doi.org/10.1186/s13229-017-0175-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331
in Molecular Autism > 8 (2017) . - 59p.[article] Mutations in RAB39B in individuals with intellectual disability, autism spectrum disorder, and macrocephaly [Texte imprimé et/ou numérique] / M. WOODBURY-SMITH, Auteur ; E. DENEAULT, Auteur ; R. K. C. YUEN, Auteur ; S. WALKER, Auteur ; M. ZARREI, Auteur ; G. PELLECCHIA, Auteur ; J. L. HOWE, Auteur ; N. HOANG, Auteur ; M. UDDIN, Auteur ; C. R. MARSHALL, Auteur ; C. CHRYSLER, Auteur ; A. THOMPSON, Auteur ; P. SZATMARI, Auteur ; Stephen SCHERER, Auteur . - 59p.
Langues : Anglais (eng)
in Molecular Autism > 8 (2017) . - 59p.
Mots-clés : Intellectual disability (ID) Rab39b RNAseq Whole genome sequencing (WGS) Index. décimale : PER Périodiques Résumé : Background: Autism spectrum disorder (ASD), a developmental disorder of early childhood onset, affects males four times more frequently than females, suggesting a role for the sex chromosomes. In this study, we describe a family with ASD in which a predicted pathogenic nonsense mutation in the X-chromosome gene RAB39B segregates with ASD phenotype. Methods: Clinical phenotyping, microarray, and whole genome sequencing (WGS) were performed on the five members of this family. Maternal and female sibling X inactivation ratio was calculated, and phase was investigated. Mutant-induced pluripotent stem cells engineered for an exon 2 nonsense mutation were generated and differentiated into cortical neurons for expression and pathway analyses. Results: Two males with an inherited RAB39B mutation both presented with macrocephaly, intellectual disability (ID), and ASD. Their female sibling with the same mutation presented with ID and a broad autism phenotype. In contrast, their transmitting mother has no neurodevelopmental diagnosis. Our investigation of phase indicated maternal preferential inactivation of the mutated allele, with no such bias observed in the female sibling. We offer the explanation that this bias in X inactivation may explain the absence of a neurocognitive phenotype in the mother. Our cellular knockout model of RAB39B revealed an impact on expression in differentiated neurons for several genes implicated in brain development and function, supported by our pathway enrichment analysis. Conclusions: Penetrance for ASD is high among males but more variable among females with RAB39B mutations. A critical role for this gene in brain development and function is demonstrated. En ligne : http://dx.doi.org/10.1186/s13229-017-0175-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331