Genetics of Human Developmental Brain Disorders
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ABSTRACT:
PROVIDER: PRJNA160053 | ENA |
REPOSITORIES: ENA
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Project description:<p>Developmental brain malformations are at the core of significant neurological diseases affecting many families in the United States and around the world. It is known that epilepsy, specific learning deficits and intellectual disability, cerebral palsy, and abnormalities of brain volume can be attributed in many cases to pathological malformations of the cerebral cortex. Although these consequences, such as epilepsy and intellectual disability, might appear broadly in the population as due to complex traits, this study's focus on those associated with cortical malformations highlights individual developmental pathways likely represented by innumerable and rare Mendelian alleles. Research has thus far uncovered dozens of genes responsible for these conditions and dissected the mechanisms underlying early cortical development in animals. However, this progress represents only the dawn of understanding the complex genetic network and neuronal architecture of the uniquely human cerebral cortex.</p> <p>The overall goal of this study is to define the genetic bases of human cerebral cortical development. This is accomplished through (1) the ascertainment of families with disorders of human brain development and malformation, (2) categorizing these using medical, physical and neuroimaging data, and (3) mapping and identifying the gene causing the disorder of cortical development, which can then be investigated for its normal expression and function, and role in human disease.</p>
| phs000492.v1.p1 | EGA
Project description:The postsynaptic density (PSD) contains a collection of scaffold proteins used for the assembly of synaptic signaling complexes and disruption of this signaling machinery might be implicated in a variety of brain disorders. However, it is not known how the core-scaffold machinery associates this collection of proteins through development and how proteins coding for genes involved in psychiatric and other brain disorders are distributed through spatio-temporal protein complexes. Here, using immunopurification, proteomics, bioinformatics and mouse genetics, we isolated 2876 proteins across 41 in-vivo protein complexes and determined their protein domain composition, correlation to gene expression levels, and developmental integration to the PSD. We defined major protein clusters for enrichment of schizophrenia (SCZ), autism spectrum disorders (ASD), developmental delay (DD), and intellectual disability (ID) risk factors at embryonic day 14 and the adult PSD. These protein complexes contained a discrete number of protein domains defining molecular functions. Mutations in highly-connected nodes alter protein-protein interactions that modulate the assembly of macromolecular complexes enriched in disease risk candidates. These results were integrated into a software platform: Synaptic Protein/Pathways Resource (SyPPRes), enabling the prioritization of brain disease risk factors and their placement within synaptic protein interaction networks.
2017-08-22 | PXD006277 | Pride
Project description:<p>Developmental brain malformations are at the core of significant neurological diseases affecting many families in the United States and around the world. It is known that epilepsy, specific learning deficits and intellectual disability, cerebral palsy, and abnormalities of brain volume can be attributed in many cases to pathological malformations of the cerebral cortex. Although these consequences, such as epilepsy and intellectual disability, might appear broadly in the population as due to complex traits, this study's focus on those associated with cortical malformations highlights individual developmental pathways likely represented by innumerable and rare Mendelian alleles. Research has thus far uncovered dozens of genes responsible for these conditions and dissected the mechanisms underlying early cortical development in animals. However, this progress represents only the dawn of understanding the complex genetic network and neuronal architecture of the uniquely human cerebral cortex.</p> <p>The overall goal of this study is to define the genetic bases of human cerebral cortical development. This is accomplished through (1) the ascertainment of families with disorders of human brain development and malformation, (2) categorizing these using medical, physical and neuroimaging data, and (3) mapping and identifying the gene causing the disorder of cortical development, which can then be investigated for its normal expression and function, and role in human disease. </p>
| phs000492 | dbGaP
Project description:Role of miR-146a in mouse brain development: relevance for developmental brain disorders
| PRJNA471537 | ENA
Project description:Genetics of Mood Disorders: Aging and Emotion Regulation Brain Circuitry in Bipolar
| PRJNA476662 | ENA
Project description:Genetics of Mood Disorders: Aging and Emotion Regulation Brain Circuitry in Bipolar
| PRJNA476663 | ENA
Project description:Genetics and Pathophysiology of Autoinflammatory Disorders
| PRJNA552920 | ENA
Project description:Genetics and Pathophysiology of Autoinflammatory Disorders
| PRJNA552921 | ENA
Project description:MicroRNAs (miRNAs) are short non-coding RNAs that regulate gene expression post-transcriptionally. miRs are involved in a wide range of regulation networks, including those involved in brain development. We and other showed an upregulation of miR-146a in autism spectrum disorders, intellectual disability and epilepsy. Taking advantage of a mouse model constitutively inactivated for miR-146a, we investigated its functions during brain development using a combination of imaging, molecular, cell biology techniques and behavioral studies. We demonstrated that loss of miR-146a causes time and region specific expression defects in the mouse brain. Pyramidal and interneurons are the most severely affected cell types with deregulated pathways reflecting different stages of neuronal differentiation and synaptic maturation. We showed that absence of miR-146a impairs the balance between proliferation and differentiation of neural progenitors. We observed no difference in neither brain weight nor total volume but an increased hemispheric asymmetry of hippocampal volume. Lastly, impaired associative memory was also observed. Our results show that miR-146 is important for proper brain development and support the hypothesis that miR-146a deregulation may play a role in developmental brain disorders.
2019-06-01 | GSE114491 | GEO