Haploinsufficiency of the intellectual disability-gene SETD5 disturbs developmental gene expression and cognition
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ABSTRACT:
PROVIDER: PRJNA489423 | ENA |
REPOSITORIES: ENA
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Project description:SETD5 gene mutations have been identified as a frequent cause of idiopathic intellectual disability. Here we show that Setd5 haploinsufficient mice present developmental defects such as abnormal brain to body weight ratio and neural crest defect associated phenotypes. Furthermore, Setd5 mutant mice show impairments in cognitive tasks, enhanced long-term potentiation, delayed ontogenetic profile of ultrasonic vocalisation and behavioural inflexibility. Behavioural issues are accompanied by abnormal expression of postsynaptic density proteins previously associated with cognition. Our data suggest that Setd5 might regulate RNA polymerase II dynamics and gene transcription during development and learning via its interaction with the Hdac3 and Paf1 complexes. Our results emphasize the decisive role of Setd5 in a biological pathway found to be disrupted in intellectual disability and autism spectrum disorder patients.
2018-11-05 | GSE119498 | GEO
Project description:An increasing number of genes involved in chromatin structure and epigenetic regulation has been implicated in a variety of developmental disorders, often including intellectual disability. By trio exome sequencing and subsequent mutational screening we now identified two de novo frameshift mutations and one de novo missense mutation in the CTCF gene in individuals with intellectual disability, microcephaly and growth retardation. Furthermore, a patient with a larger deletion including CTCF was identified. CTCF (CCCTC-binding factor) is one of the most important chromatin organizers in vertebrates and is involved in various chromatin regulation processes such as higher order of chromatin organization, enhancer function, and maintenance of three-dimensional chromatin structure. Transcriptome analyses in all three patients with point mutations revealed deregulation of genes involved in signal transduction and emphasized the role of CTCF in enhancer-driven expression of genes. Our findings indicate that haploinsufficiency of CTCF affects genomic interaction of enhancers and their regulated gene promoters that drive developmental processes and cognition. Comparison of lymphocyte gene expression between 3 de novo CTCF mutation patients and 8 controls (4 technical replicates each, no biological replicates).
2013-06-01 | E-GEOD-46831 | biostudies-arrayexpress
Project description:An increasing number of genes involved in chromatin structure and epigenetic regulation has been implicated in a variety of developmental disorders, often including intellectual disability. By trio exome sequencing and subsequent mutational screening we now identified two de novo frameshift mutations and one de novo missense mutation in the CTCF gene in individuals with intellectual disability, microcephaly and growth retardation. Furthermore, a patient with a larger deletion including CTCF was identified. CTCF (CCCTC-binding factor) is one of the most important chromatin organizers in vertebrates and is involved in various chromatin regulation processes such as higher order of chromatin organization, enhancer function, and maintenance of three-dimensional chromatin structure. Transcriptome analyses in all three patients with point mutations revealed deregulation of genes involved in signal transduction and emphasized the role of CTCF in enhancer-driven expression of genes. Our findings indicate that haploinsufficiency of CTCF affects genomic interaction of enhancers and their regulated gene promoters that drive developmental processes and cognition. ChIP-seq analysis of CTCF genomic binding sites in lymphocytes of a control individual (no replicates).
2013-06-01 | E-GEOD-46832 | biostudies-arrayexpress
Project description:Identifying causes of sporadic intellectual disability remains a considerable medical challenge. Here, we demonstrate that null mutations in the NONO gene, a member of the Drosophila Behavior Human Splicing (DBHS) protein family, are a novel cause of X-linked syndromic intellectual disability. Comparing humans to Nono-deficient mice revealed related behavioral and craniofacial anomalies, as well as global transcriptional dysregulation. Nono-deficient mice also showed deregulation of a large number of synaptic transcripts, causing a disorganization of inhibitory synapses, with impaired postsynaptic scaffolding of gephyrin. Alteration of gephyrin clustering could be rescued by over-expression of Gabra2 in NONO-compromised neurons. These findings link NONO to intellectual disability and first highlight the key role of DBHS proteins in functional organization of GABAergic synapses.
2015-09-02 | E-MTAB-2895 | biostudies-arrayexpress
Project description:Identifying causes of sporadic intellectual disability remains a considerable medical challenge. Here, we demonstrate that null mutations in the NONO gene, a member of the Drosophila Behavior Human Splicing (DBHS) protein family, are a novel cause of X-linked syndromic intellectual disability. Comparing humans to Nono-deficient mice revealed related behavioral and craniofacial anomalies, as well as global transcriptional dysregulation. Nono-deficient mice also showed deregulation of a large number of synaptic transcripts, causing a disorganization of inhibitory synapses, with impaired postsynaptic scaffolding of gephyrin. Alteration of gephyrin clustering could be rescued by over-expression of Gabra2 in NONO-compromised neurons. These findings link NONO to intellectual disability and first highlight the key role of DBHS proteins in functional organization of GABAergic synapses.
2015-09-02 | E-MTAB-2894 | biostudies-arrayexpress
Project description:An increasing number of genes involved in chromatin structure and epigenetic regulation has been implicated in a variety of developmental disorders, often including intellectual disability. By trio exome sequencing and subsequent mutational screening we now identified two de novo frameshift mutations and one de novo missense mutation in the CTCF gene in individuals with intellectual disability, microcephaly and growth retardation. Furthermore, a patient with a larger deletion including CTCF was identified. CTCF (CCCTC-binding factor) is one of the most important chromatin organizers in vertebrates and is involved in various chromatin regulation processes such as higher order of chromatin organization, enhancer function, and maintenance of three-dimensional chromatin structure. Transcriptome analyses in all three patients with point mutations revealed deregulation of genes involved in signal transduction and emphasized the role of CTCF in enhancer-driven expression of genes. Our findings indicate that haploinsufficiency of CTCF affects genomic interaction of enhancers and their regulated gene promoters that drive developmental processes and cognition.
2013-06-01 | GSE46832 | GEO
Project description:An increasing number of genes involved in chromatin structure and epigenetic regulation has been implicated in a variety of developmental disorders, often including intellectual disability. By trio exome sequencing and subsequent mutational screening we now identified two de novo frameshift mutations and one de novo missense mutation in the CTCF gene in individuals with intellectual disability, microcephaly and growth retardation. Furthermore, a patient with a larger deletion including CTCF was identified. CTCF (CCCTC-binding factor) is one of the most important chromatin organizers in vertebrates and is involved in various chromatin regulation processes such as higher order of chromatin organization, enhancer function, and maintenance of three-dimensional chromatin structure. Transcriptome analyses in all three patients with point mutations revealed deregulation of genes involved in signal transduction and emphasized the role of CTCF in enhancer-driven expression of genes. Our findings indicate that haploinsufficiency of CTCF affects genomic interaction of enhancers and their regulated gene promoters that drive developmental processes and cognition.
2013-06-01 | GSE46831 | GEO
Project description:10 patients with Intellectual Disability diagnosed with a clinically relevant copy number change, selected to assess the dection performance of alternative platforms.
2013-08-01 | GSE46060 | GEO
Project description:10 patients with Intellectual Disability diagnosed with a clinically relevant copy number change, selected to assess the dection performance of alternative platforms. 10 Affymetrix arrays were performed according to the manufacturer's directions on DNA extracted from peripheral blood samples.
2013-08-01 | E-GEOD-46060 | biostudies-arrayexpress
Project description:Intellectual disability is a common condition that carries lifelong severe medical and developmental consequences. The causes of intellectual disability (ID) remain unknown for the majority of patients due to the extensive clinical and genetic heterogeneity of this disorder. De novo mutations may play an important role in ID as most individuals with ID present as isolated cases without family history and/or clear syndromic indication. In addition, the involvement of such mutations have recently been demonstrated in a small number of individuals with ID. Here we evaluate the diagnostic potential and role of de novo mutations in a cohort of 100 patients with ID of unknown cause using family-based exome sequencing. Single end short-read (50 bp) SOLiD 4 sequencing data for 300 individuals, constituting 100 patient-parent trios. For more details please read; http://www.nejm.org/doi/full/10.1056/NEJMoa1206524. Dataset is created by RUNMC (Radboud University, Nijmegen Medical Center), partner of Geuvadis consortium (http://www.geuvadis.org).
2013-11-06 | E-GEUV-5 | biostudies-arrayexpress