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Discovery of autism/intellectual disability somatic mutations in Alzheimer's brains: mutated ADNP cytoskeletal impairments and repair as a case study

ABSTRACT: Discovery of autism/intellectual disability somatic mutations in Alzheimer's brains: mutated ADNP cytoskeletal impairments and repair as a case study

PROVIDER: PRJNA451437 | ENA |

REPOSITORIES: ENA

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Discovery of autism/intellectual disability somatic mutations in Alzheimer's brains: mutated ADNP cytoskeletal impairments and repair as a case study

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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.

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Project description:Intellectual disability (ID) is a clinically important disease and a most prevalent neurodevelopmental disorder. The etiology and pathogenesis of ID are poorly recognized. Exome sequencing revealed a homozygous missense mutation in the POLR3B gene in a consanguineous family with three Intellectual disability with craniofacal anomalies patients. POLR3B gene encoding the second largest subunit of RNA polymerase III. To explore how genetic variants alter cell expression in ID patients, RNA sequencing on blood samples was performed and to obtain insights into the biological pathways influenced by POLR3B mutation, we applied our RNA-Seq data to several gene ontology programs such as ToppGene, Enrichr, KEGG. We detected a significant decrease expression of several spliceosomal RNAs, ribosomal proteins and transcription factors in our ID patients. We hypothesize that POLR3B mutation dysregulates the expression of some important transcription factors, ribosomal and spliceosomal genes and impairments in protein synthesis and splicing mediated in part by transcription factors such as FOXC2, GATA1, .. contribute to impaired neuronal function and concurrence of intellectual disability and craniofacial anomalies in our patients. Our study highlights the emerging role of spliceosome and ribosomal proteins in intellectual disability.

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NONO mutations cause syndromic intellectual disability and inhibitory synaptic defects

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Transcriptome analysis of Adnp-heterozygous mice in the hippocampus

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Discovery of autism/intellectual disability somatic mutations in Alzheimer's brains: mutated ADNP cytoskeletal impairments and repair as a case study.

Project description: Not available

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Diagnostic Exome Sequencing in Persons with Severe Intellectual Disability.

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).

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