Characterization of cell-cell communication in autistic brains with single-cell transcriptomes / Maider ASTORKIA in Journal of Neurodevelopmental Disorders, 14 (2022)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 14 (2022) Titre : Characterization of cell-cell communication in autistic brains with single-cell transcriptomes Type de document : texte imprimé Auteurs : Maider ASTORKIA, Auteur ; Herbert M. LACHMAN, Auteur ; Deyou ZHENG, Auteur Langues : Anglais (eng) Mots-clés : Autism Spectrum Disorder/pathology  Autistic Disorder/genetics  Brain/pathology  Cell Communication  Child  Humans  Transcriptome  Autism  Brain  Cell-cell communication  Ligand-receptor  Network  Single-cell RNA-seq Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder is a neurodevelopmental disorder, affecting 1-2% of children. Studies have revealed genetic and cellular abnormalities in the brains of affected individuals, leading to both regional and distal cell communication deficits. METHODS: Recent application of single-cell technologies, especially single-cell transcriptomics, has significantly expanded our understanding of brain cell heterogeneity and further demonstrated that multiple cell types and brain layers or regions are perturbed in autism. The underlying high-dimensional single-cell data provides opportunities for multilevel computational analysis that collectively can better deconvolute the molecular and cellular events altered in autism. Here, we apply advanced computation and pattern recognition approaches on single-cell RNA-seq data to infer and compare inter-cell-type signaling communications in autism brains and controls. RESULTS: Our results indicate that at a global level, there are cell-cell communication differences in autism in comparison with controls, largely involving neurons as both signaling senders and receivers, but glia also contribute to the communication disruption. Although the magnitude of changes is moderate, we find that excitatory and inhibitor neurons are involved in multiple intercellular signaling that exhibits increased strengths in autism, such as NRXN and CNTN signaling. Not all genes in the intercellular signaling pathways show differential expression, but genes in the affected pathways are enriched for axon guidance, synapse organization, neuron migration, and other critical cellular functions. Furthermore, those genes are highly connected to and enriched for genes previously associated with autism risks. CONCLUSIONS: Overall, our proof-of-principle computational study using single-cell data uncovers key intercellular signaling pathways that are potentially disrupted in the autism brains, suggesting that more studies examining cross-cell type effects can be valuable for understanding autism pathogenesis. En ligne : https://dx.doi.org/10.1186/s11689-022-09441-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=574 [article] Characterization of cell-cell communication in autistic brains with single-cell transcriptomes [texte imprimé] / Maider ASTORKIA, Auteur ; Herbert M. LACHMAN, Auteur ; Deyou ZHENG, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 14 (2022) Mots-clés : Autism Spectrum Disorder/pathology  Autistic Disorder/genetics  Brain/pathology  Cell Communication  Child  Humans  Transcriptome  Autism  Brain  Cell-cell communication  Ligand-receptor  Network  Single-cell RNA-seq Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder is a neurodevelopmental disorder, affecting 1-2% of children. Studies have revealed genetic and cellular abnormalities in the brains of affected individuals, leading to both regional and distal cell communication deficits. METHODS: Recent application of single-cell technologies, especially single-cell transcriptomics, has significantly expanded our understanding of brain cell heterogeneity and further demonstrated that multiple cell types and brain layers or regions are perturbed in autism. The underlying high-dimensional single-cell data provides opportunities for multilevel computational analysis that collectively can better deconvolute the molecular and cellular events altered in autism. Here, we apply advanced computation and pattern recognition approaches on single-cell RNA-seq data to infer and compare inter-cell-type signaling communications in autism brains and controls. RESULTS: Our results indicate that at a global level, there are cell-cell communication differences in autism in comparison with controls, largely involving neurons as both signaling senders and receivers, but glia also contribute to the communication disruption. Although the magnitude of changes is moderate, we find that excitatory and inhibitor neurons are involved in multiple intercellular signaling that exhibits increased strengths in autism, such as NRXN and CNTN signaling. Not all genes in the intercellular signaling pathways show differential expression, but genes in the affected pathways are enriched for axon guidance, synapse organization, neuron migration, and other critical cellular functions. Furthermore, those genes are highly connected to and enriched for genes previously associated with autism risks. CONCLUSIONS: Overall, our proof-of-principle computational study using single-cell data uncovers key intercellular signaling pathways that are potentially disrupted in the autism brains, suggesting that more studies examining cross-cell type effects can be valuable for understanding autism pathogenesis. En ligne : https://dx.doi.org/10.1186/s11689-022-09441-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=574

CRISPR/Cas9-mediated heterozygous knockout of the autism gene CHD8 and characterization of its transcriptional networks in cerebral organoids derived from iPS cells / Ping WANG in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 11p. Titre : CRISPR/Cas9-mediated heterozygous knockout of the autism gene CHD8 and characterization of its transcriptional networks in cerebral organoids derived from iPS cells Type de document : texte imprimé Auteurs : Ping WANG, Auteur ; Ryan MOKHTARI, Auteur ; Erika PEDROSA, Auteur ; Michael KIRSCHENBAUM, Auteur ; Can BAYRAK, Auteur ; Deyou ZHENG, Auteur ; Herbert M. LACHMAN, Auteur Article en page(s) : 11p. Langues : Anglais (eng) Mots-clés : Autism Spectrum Disorder/genetics  Bipolar Disorder/genetics  CRISPR-Cas Systems  Cell Differentiation  Cells, Cultured  DNA-Binding Proteins/*genetics  Gene Expression Profiling/*methods  Gene Expression Regulation  Gene Knockout Techniques  *Gene Regulatory Networks  Humans  Induced Pluripotent Stem Cells/*cytology  Mental Disorders/*genetics  Mutation  Organoids/*cytology  Schizophrenia/genetics  Sequence Analysis, RNA/*methods  Telencephalon/*cytology  Transcription Factors/*genetics  *Autism  *Beta-catenin  *Bipolar disorder  *Cancer  *Dlx6-as1  *Distal-less homeobox  *Gabaergic  *Hmga2  *Schizophrenia  *Tcf4  *Wnt  *Znf132 Index. décimale : PER Périodiques Résumé : BACKGROUND: CHD8 (chromodomain helicase DNA-binding protein 8), which codes for a member of the CHD family of ATP-dependent chromatin-remodeling factors, is one of the most commonly mutated genes in autism spectrum disorders (ASD) identified in exome-sequencing studies. Loss of function mutations in the gene have also been found in schizophrenia (SZ) and intellectual disabilities and influence cancer cell proliferation. We previously reported an RNA-seq analysis carried out on neural progenitor cells (NPCs) and monolayer neurons derived from induced pluripotent stem (iPS) cells that were heterozygous for CHD8 knockout (KO) alleles generated using CRISPR-Cas9 gene editing. A significant number of ASD and SZ candidate genes were among those that were differentially expressed in a comparison of heterozygous KO lines (CHD8(+/-)) vs isogenic controls (CHD8(+/-)), including the SZ and bipolar disorder (BD) candidate gene TCF4, which was markedly upregulated in CHD8(+/-) neuronal cells. METHODS: In the current study, RNA-seq was carried out on CHD8(+/-) and isogenic control (CHD8(+/+)) cerebral organoids, which are 3-dimensional structures derived from iPS cells that model the developing human telencephalon. RESULTS: TCF4 expression was, again, significantly upregulated. Pathway analysis carried out on differentially expressed genes (DEGs) revealed an enrichment of genes involved in neurogenesis, neuronal differentiation, forebrain development, Wnt/beta-catenin signaling, and axonal guidance, similar to our previous study on NPCs and monolayer neurons. There was also significant overlap in our CHD8(+/-) DEGs with those found in a transcriptome analysis carried out by another group using cerebral organoids derived from a family with idiopathic ASD. Remarkably, the top DEG in our respective studies was the non-coding RNA DLX6-AS1, which was markedly upregulated in both studies; DLX6-AS1 regulates the expression of members of the DLX (distal-less homeobox) gene family. DLX1 was also upregulated in both studies. DLX genes code for transcription factors that play a key role in GABAergic interneuron differentiation. Significant overlap was also found in a transcriptome study carried out by another group using iPS cell-derived neurons from patients with BD, a condition characterized by dysregulated WNT/beta-catenin signaling in a subgroup of affected individuals. CONCLUSIONS: Overall, the findings show that distinct ASD, SZ, and BD candidate genes converge on common molecular targets-an important consideration for developing novel therapeutics in genetically heterogeneous complex traits. En ligne : http://dx.doi.org/10.1186/s13229-017-0124-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331 [article] CRISPR/Cas9-mediated heterozygous knockout of the autism gene CHD8 and characterization of its transcriptional networks in cerebral organoids derived from iPS cells [texte imprimé] / Ping WANG, Auteur ; Ryan MOKHTARI, Auteur ; Erika PEDROSA, Auteur ; Michael KIRSCHENBAUM, Auteur ; Can BAYRAK, Auteur ; Deyou ZHENG, Auteur ; Herbert M. LACHMAN, Auteur . - 11p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 11p. Mots-clés : Autism Spectrum Disorder/genetics  Bipolar Disorder/genetics  CRISPR-Cas Systems  Cell Differentiation  Cells, Cultured  DNA-Binding Proteins/*genetics  Gene Expression Profiling/*methods  Gene Expression Regulation  Gene Knockout Techniques  *Gene Regulatory Networks  Humans  Induced Pluripotent Stem Cells/*cytology  Mental Disorders/*genetics  Mutation  Organoids/*cytology  Schizophrenia/genetics  Sequence Analysis, RNA/*methods  Telencephalon/*cytology  Transcription Factors/*genetics  *Autism  *Beta-catenin  *Bipolar disorder  *Cancer  *Dlx6-as1  *Distal-less homeobox  *Gabaergic  *Hmga2  *Schizophrenia  *Tcf4  *Wnt  *Znf132 Index. décimale : PER Périodiques Résumé : BACKGROUND: CHD8 (chromodomain helicase DNA-binding protein 8), which codes for a member of the CHD family of ATP-dependent chromatin-remodeling factors, is one of the most commonly mutated genes in autism spectrum disorders (ASD) identified in exome-sequencing studies. Loss of function mutations in the gene have also been found in schizophrenia (SZ) and intellectual disabilities and influence cancer cell proliferation. We previously reported an RNA-seq analysis carried out on neural progenitor cells (NPCs) and monolayer neurons derived from induced pluripotent stem (iPS) cells that were heterozygous for CHD8 knockout (KO) alleles generated using CRISPR-Cas9 gene editing. A significant number of ASD and SZ candidate genes were among those that were differentially expressed in a comparison of heterozygous KO lines (CHD8(+/-)) vs isogenic controls (CHD8(+/-)), including the SZ and bipolar disorder (BD) candidate gene TCF4, which was markedly upregulated in CHD8(+/-) neuronal cells. METHODS: In the current study, RNA-seq was carried out on CHD8(+/-) and isogenic control (CHD8(+/+)) cerebral organoids, which are 3-dimensional structures derived from iPS cells that model the developing human telencephalon. RESULTS: TCF4 expression was, again, significantly upregulated. Pathway analysis carried out on differentially expressed genes (DEGs) revealed an enrichment of genes involved in neurogenesis, neuronal differentiation, forebrain development, Wnt/beta-catenin signaling, and axonal guidance, similar to our previous study on NPCs and monolayer neurons. There was also significant overlap in our CHD8(+/-) DEGs with those found in a transcriptome analysis carried out by another group using cerebral organoids derived from a family with idiopathic ASD. Remarkably, the top DEG in our respective studies was the non-coding RNA DLX6-AS1, which was markedly upregulated in both studies; DLX6-AS1 regulates the expression of members of the DLX (distal-less homeobox) gene family. DLX1 was also upregulated in both studies. DLX genes code for transcription factors that play a key role in GABAergic interneuron differentiation. Significant overlap was also found in a transcriptome study carried out by another group using iPS cell-derived neurons from patients with BD, a condition characterized by dysregulated WNT/beta-catenin signaling in a subgroup of affected individuals. CONCLUSIONS: Overall, the findings show that distinct ASD, SZ, and BD candidate genes converge on common molecular targets-an important consideration for developing novel therapeutics in genetically heterogeneous complex traits. En ligne : http://dx.doi.org/10.1186/s13229-017-0124-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331

CRISPR/Cas9-mediated heterozygous knockout of the autism gene CHD8 and characterization of its transcriptional networks in neurodevelopment / Ping WANG in Molecular Autism, (October 2015)  

Public ISBD [article]  inMolecular Autism > (October 2015) . - p.1-18 Titre : CRISPR/Cas9-mediated heterozygous knockout of the autism gene CHD8 and characterization of its transcriptional networks in neurodevelopment Type de document : texte imprimé Auteurs : Ping WANG, Auteur ; Mingyan LIN, Auteur ; Erika PEDROSA, Auteur ; Anastasia HRABOVSKY, Auteur ; Zheng ZHANG, Auteur ; Wenjun GUO, Auteur ; Herbert M. LACHMAN, Auteur ; Deyou ZHENG, Auteur Article en page(s) : p.1-18 Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Disruptive mutation in the CHD8 gene is one of the top genetic risk factors in autism spectrum disorders (ASDs). Previous analyses of genome-wide CHD8 occupancy and reduced expression of CHD8 by shRNA knockdown in committed neural cells showed that CHD8 regulates multiple cell processes critical for neural functions, and its targets are enriched with ASD-associated genes. En ligne : http://dx.doi.org/10.1186/s13229-015-0048-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=277 [article] CRISPR/Cas9-mediated heterozygous knockout of the autism gene CHD8 and characterization of its transcriptional networks in neurodevelopment [texte imprimé] / Ping WANG, Auteur ; Mingyan LIN, Auteur ; Erika PEDROSA, Auteur ; Anastasia HRABOVSKY, Auteur ; Zheng ZHANG, Auteur ; Wenjun GUO, Auteur ; Herbert M. LACHMAN, Auteur ; Deyou ZHENG, Auteur . - p.1-18. Langues : Anglais (eng) in Molecular Autism > (October 2015) . - p.1-18 Index. décimale : PER Périodiques Résumé : Disruptive mutation in the CHD8 gene is one of the top genetic risk factors in autism spectrum disorders (ASDs). Previous analyses of genome-wide CHD8 occupancy and reduced expression of CHD8 by shRNA knockdown in committed neural cells showed that CHD8 regulates multiple cell processes critical for neural functions, and its targets are enriched with ASD-associated genes. En ligne : http://dx.doi.org/10.1186/s13229-015-0048-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=277

Transcriptome analysis of microglia in a mouse model of Rett syndrome: differential expression of genes associated with microglia/macrophage activation and cellular stress / Dejian ZHAO in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 17p. Titre : Transcriptome analysis of microglia in a mouse model of Rett syndrome: differential expression of genes associated with microglia/macrophage activation and cellular stress Type de document : texte imprimé Auteurs : Dejian ZHAO, Auteur ; Ryan MOKHTARI, Auteur ; Erika PEDROSA, Auteur ; Rayna BIRNBAUM, Auteur ; Deyou ZHENG, Auteur ; Herbert M. LACHMAN, Auteur Article en page(s) : 17p. Langues : Anglais (eng) Mots-clés : Animals  Disease Models, Animal  Female  Gene Expression Profiling/*methods  Gene Expression Regulation  Heat-Shock Proteins/genetics  Humans  Macrophage Activation  Macrophages/*cytology  Methyl-CpG-Binding Protein 2/*deficiency  Mice  Microglia/*metabolism  Mutation  Oxidative Stress  Rett Syndrome/*genetics  Sequence Analysis, RNA/*methods  *Autism  *Heat shock  *Innate immune system  *M1 activation  *M2 activation  *Microglia  *Rett syndrome  *Schizophrenia Index. décimale : PER Périodiques Résumé : BACKGROUND: Rett syndrome (RTT) is a severe, neurodevelopmental disorder primarily affecting girls, characterized by progressive loss of cognitive, social, and motor skills after a relatively brief period of typical development. It is usually due to de novo loss of function mutations in the X-linked gene, MeCP2, which codes for the gene expression and chromatin regulator, methyl-CpG binding protein 2. Although the behavioral phenotype appears to be primarily due to neuronal Mecp2 deficiency in mice, other cell types, including astrocytes and oligodendrocytes, also appear to contribute to some aspects of the RTT phenotype. In addition, microglia may also play a role. However, the effect of Mecp2 deficiency in microglia on RTT pathogenesis is controversial. METHODS: In the current study, we applied whole transcriptome analysis using RNA-seq to gain insight into molecular pathways in microglia that might be dysregulated during the transition, in female mice heterozygous for an Mecp2-null allele (Mecp2(+/-); Het), from the pre-phenotypic (5 weeks) to the phenotypic phases (24 weeks). RESULTS: We found a significant overlap in differentially expressed genes (DEGs) with genes involved in regulating the extracellular matrix, and those that are activated or inhibited when macrophages and microglia are stimulated towards the M1 and M2 activation states. However, the M1- and M2-associated genes were different in the 5- and 24-week samples. In addition, a substantial decrease in the expression of nine members of the heat shock protein (HSP) family was found in the 5-week samples, but not at 24 weeks. CONCLUSIONS: These findings suggest that microglia from pre-phenotypic and phenotypic female mice are activated in a manner different from controls and that pre-phenotypic female mice may have alterations in their capacity to response to heat stress and other stressors that function through the HSP pathway. En ligne : http://dx.doi.org/10.1186/s13229-017-0134-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331 [article] Transcriptome analysis of microglia in a mouse model of Rett syndrome: differential expression of genes associated with microglia/macrophage activation and cellular stress [texte imprimé] / Dejian ZHAO, Auteur ; Ryan MOKHTARI, Auteur ; Erika PEDROSA, Auteur ; Rayna BIRNBAUM, Auteur ; Deyou ZHENG, Auteur ; Herbert M. LACHMAN, Auteur . - 17p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 17p. Mots-clés : Animals  Disease Models, Animal  Female  Gene Expression Profiling/*methods  Gene Expression Regulation  Heat-Shock Proteins/genetics  Humans  Macrophage Activation  Macrophages/*cytology  Methyl-CpG-Binding Protein 2/*deficiency  Mice  Microglia/*metabolism  Mutation  Oxidative Stress  Rett Syndrome/*genetics  Sequence Analysis, RNA/*methods  *Autism  *Heat shock  *Innate immune system  *M1 activation  *M2 activation  *Microglia  *Rett syndrome  *Schizophrenia Index. décimale : PER Périodiques Résumé : BACKGROUND: Rett syndrome (RTT) is a severe, neurodevelopmental disorder primarily affecting girls, characterized by progressive loss of cognitive, social, and motor skills after a relatively brief period of typical development. It is usually due to de novo loss of function mutations in the X-linked gene, MeCP2, which codes for the gene expression and chromatin regulator, methyl-CpG binding protein 2. Although the behavioral phenotype appears to be primarily due to neuronal Mecp2 deficiency in mice, other cell types, including astrocytes and oligodendrocytes, also appear to contribute to some aspects of the RTT phenotype. In addition, microglia may also play a role. However, the effect of Mecp2 deficiency in microglia on RTT pathogenesis is controversial. METHODS: In the current study, we applied whole transcriptome analysis using RNA-seq to gain insight into molecular pathways in microglia that might be dysregulated during the transition, in female mice heterozygous for an Mecp2-null allele (Mecp2(+/-); Het), from the pre-phenotypic (5 weeks) to the phenotypic phases (24 weeks). RESULTS: We found a significant overlap in differentially expressed genes (DEGs) with genes involved in regulating the extracellular matrix, and those that are activated or inhibited when macrophages and microglia are stimulated towards the M1 and M2 activation states. However, the M1- and M2-associated genes were different in the 5- and 24-week samples. In addition, a substantial decrease in the expression of nine members of the heat shock protein (HSP) family was found in the 5-week samples, but not at 24 weeks. CONCLUSIONS: These findings suggest that microglia from pre-phenotypic and phenotypic female mice are activated in a manner different from controls and that pre-phenotypic female mice may have alterations in their capacity to response to heat stress and other stressors that function through the HSP pathway. En ligne : http://dx.doi.org/10.1186/s13229-017-0134-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331

Transcriptome analysis of neural progenitor cells derived from Lowe syndrome induced pluripotent stem cells: identification of candidate genes for the neurodevelopmental and eye manifestations / Hequn LIU in Journal of Neurodevelopmental Disorders, 12 (2020)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 12 (2020) Titre : Transcriptome analysis of neural progenitor cells derived from Lowe syndrome induced pluripotent stem cells: identification of candidate genes for the neurodevelopmental and eye manifestations Type de document : texte imprimé Auteurs : Hequn LIU, Auteur ; Jesse BARNES, Auteur ; Erika PEDROSA, Auteur ; Nathaniel S. HERMAN, Auteur ; Franklin SALAS, Auteur ; Ping WANG, Auteur ; Deyou ZHENG, Auteur ; Herbert M. LACHMAN, Auteur Langues : Anglais (eng) Mots-clés : Adolescent  Adult  Cataract/genetics  Cells, Cultured  Child  Endosomes/metabolism  Extracellular Matrix Proteins/genetics  Eye Diseases/genetics  Gene Expression Profiling  Glaucoma/genetics  Humans  Induced Pluripotent Stem Cells/metabolism  Male  Mutation  Neural Stem Cells/metabolism  Oculocerebrorenal Syndrome/genetics/metabolism/physiopathology  Phosphoric Monoester Hydrolases/genetics/metabolism  Reelin Protein  Sequence Analysis, RNA  Young Adult  Cataracts  Dpp10  Dent disease  Efemp1  Glaucoma  Kv4.2  Lowe syndrome  Meis2  Macular degeneration  Ocrl  Spon1  Tmem132 Index. décimale : PER Périodiques Résumé : BACKGROUND: Lowe syndrome (LS) is caused by loss-of-function mutations in the X-linked gene OCRL, which codes for an inositol polyphosphate 5-phosphatase that plays a key role in endosome recycling, clathrin-coated pit formation, and actin polymerization. It is characterized by congenital cataracts, intellectual and developmental disability, and renal proximal tubular dysfunction. Patients are also at high risk for developing glaucoma and seizures. We recently developed induced pluripotent stem cell (iPSC) lines from three patients with LS who have hypomorphic variants affecting the 3' end of the gene, and their neurotypical brothers to serve as controls. METHODS: In this study, we used RNA sequencing (RNA-seq) to obtain transcriptome profiles in LS and control neural progenitor cells (NPCs). RESULTS: In a comparison of the patient and control NPCs (n = 3), we found 16 differentially expressed genes (DEGs) at the multiple test adjusted p value (padj) < 0.1, with nine at padj < 0.05. Using nominal p value < 0.05, 319 DEGs were detected. The relatively small number of DEGs could be due to the fact that OCRL is not a transcription factor per se, although it could have secondary effects on gene expression through several different mechanisms. Although the number of DEGs passing multiple test correction was small, those that were found are quite consistent with some of the known molecular effects of OCRL protein, and the clinical manifestations of LS. Furthermore, using gene set enrichment analysis (GSEA), we found that genes increased expression in the patient NPCs showed enrichments of several gene ontology (GO) terms (false discovery rate < 0.25): telencephalon development, pallium development, NPC proliferation, and cortex development, which are consistent with a condition characterized by intellectual disabilities and psychiatric manifestations. In addition, a significant enrichment among the nominal DEGs for genes implicated in autism spectrum disorder (ASD) was found (e.g., AFF2, DNER, DPP6, DPP10, RELN, CACNA1C), as well as several that are strong candidate genes for the development of eye problems found in LS, including glaucoma. The most notable example is EFEMP1, a well-known candidate gene for glaucoma and other eye pathologies. CONCLUSION: Overall, the RNA-seq findings present several candidate genes that could help explain the underlying basis for the neurodevelopmental and eye problems seen in boys with LS. En ligne : https://dx.doi.org/10.1186/s11689-020-09317-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=573 [article] Transcriptome analysis of neural progenitor cells derived from Lowe syndrome induced pluripotent stem cells: identification of candidate genes for the neurodevelopmental and eye manifestations [texte imprimé] / Hequn LIU, Auteur ; Jesse BARNES, Auteur ; Erika PEDROSA, Auteur ; Nathaniel S. HERMAN, Auteur ; Franklin SALAS, Auteur ; Ping WANG, Auteur ; Deyou ZHENG, Auteur ; Herbert M. LACHMAN, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 12 (2020) Mots-clés : Adolescent  Adult  Cataract/genetics  Cells, Cultured  Child  Endosomes/metabolism  Extracellular Matrix Proteins/genetics  Eye Diseases/genetics  Gene Expression Profiling  Glaucoma/genetics  Humans  Induced Pluripotent Stem Cells/metabolism  Male  Mutation  Neural Stem Cells/metabolism  Oculocerebrorenal Syndrome/genetics/metabolism/physiopathology  Phosphoric Monoester Hydrolases/genetics/metabolism  Reelin Protein  Sequence Analysis, RNA  Young Adult  Cataracts  Dpp10  Dent disease  Efemp1  Glaucoma  Kv4.2  Lowe syndrome  Meis2  Macular degeneration  Ocrl  Spon1  Tmem132 Index. décimale : PER Périodiques Résumé : BACKGROUND: Lowe syndrome (LS) is caused by loss-of-function mutations in the X-linked gene OCRL, which codes for an inositol polyphosphate 5-phosphatase that plays a key role in endosome recycling, clathrin-coated pit formation, and actin polymerization. It is characterized by congenital cataracts, intellectual and developmental disability, and renal proximal tubular dysfunction. Patients are also at high risk for developing glaucoma and seizures. We recently developed induced pluripotent stem cell (iPSC) lines from three patients with LS who have hypomorphic variants affecting the 3' end of the gene, and their neurotypical brothers to serve as controls. METHODS: In this study, we used RNA sequencing (RNA-seq) to obtain transcriptome profiles in LS and control neural progenitor cells (NPCs). RESULTS: In a comparison of the patient and control NPCs (n = 3), we found 16 differentially expressed genes (DEGs) at the multiple test adjusted p value (padj) < 0.1, with nine at padj < 0.05. Using nominal p value < 0.05, 319 DEGs were detected. The relatively small number of DEGs could be due to the fact that OCRL is not a transcription factor per se, although it could have secondary effects on gene expression through several different mechanisms. Although the number of DEGs passing multiple test correction was small, those that were found are quite consistent with some of the known molecular effects of OCRL protein, and the clinical manifestations of LS. Furthermore, using gene set enrichment analysis (GSEA), we found that genes increased expression in the patient NPCs showed enrichments of several gene ontology (GO) terms (false discovery rate < 0.25): telencephalon development, pallium development, NPC proliferation, and cortex development, which are consistent with a condition characterized by intellectual disabilities and psychiatric manifestations. In addition, a significant enrichment among the nominal DEGs for genes implicated in autism spectrum disorder (ASD) was found (e.g., AFF2, DNER, DPP6, DPP10, RELN, CACNA1C), as well as several that are strong candidate genes for the development of eye problems found in LS, including glaucoma. The most notable example is EFEMP1, a well-known candidate gene for glaucoma and other eye pathologies. CONCLUSION: Overall, the RNA-seq findings present several candidate genes that could help explain the underlying basis for the neurodevelopmental and eye problems seen in boys with LS. En ligne : https://dx.doi.org/10.1186/s11689-020-09317-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=573

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