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Recent genetic data on schizophrenia (SCZ) have suggested that proteins of the postsynaptic density of excitatory synapses have a role in its etiology. Mutations in the three SHANK genes encoding for postsynaptic scaffolding proteins have been shown to represent risk factors for autism spectrum disorders and other neurodevelopmental disorders. To address if SHANK2 variants are associated with SCZ, we sequenced SHANK2 in 481 patients and 659 unaffected individuals. We identified a significant increase in the number of rare (minor allele frequency<1%) SHANK2 missense variants in SCZ individuals (6.9%) compared with controls (3.9%, P=0.039). Four out of fifteen non-synonymous variants identified in the SCZ cohort (S610Y, R958S, P1119T and A1731S) were selected for functional analysis. Overexpression and knockdown-rescue experiments were carried out in cultured primary hippocampal neurons with a major focus on the analysis of morphological changes. Furthermore, the effect on actin polymerization in fibroblast cell lines was investigated. All four variants revealed functional impairment to various degrees, as a consequence of alterations in spine volume and clustering at synapses and an overall loss of presynaptic contacts. The A1731S variant was identified in four unrelated SCZ patients (0.83%) but not in any of the sequenced controls and public databases (P=4.6 × 10(-5)). Patients with the A1731S variant share an early prodromal phase with an insidious onset of psychiatric symptoms. A1731S overexpression strongly decreased the SHANK2-Bassoon-positive synapse number and diminished the F/G-actin ratio. Our results strongly suggest a causative role of rare SHANK2 variants in SCZ and underline the contribution of SHANK2 gene mutations in a variety of neuropsychiatric disorders.
Pubmed ID: 25560758 RIS Download
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Digital image processing system where microscope settings and processing steps may be adjusted in single user interface. Can acquire images from variety of cameras. Includes software package for capturing, archiving and preparing images for publication. Allows users to visualize and present images in several dimensions. Functionality of imaging toolbox expands constantly with wide range of different modules that are tailored to specific applications or microscope accessories. This resource is duplicated by SCR_018376
View all literature mentionsA national mouse monoclonal antibody generating resource for biochemical and immunohistochemical applications in mammalian brain. NeuroMabs are generated from mice immunized with synthetic and recombinant immunogens corresponding to components of the neuronal proteome as predicted from genomic and other large-scale cloning efforts. Comprehensive biochemical and immunohistochemical analyses of human, primate and non-primate mammalian brain are incorporated into the initial NeuroMab screening procedure. This yields a subset of mouse mAbs that are optimized for use in brain (i.e. NeuroMabs): for immunocytochemical-based imaging studies of protein localization in adult, developing and pathological brain samples, for biochemical analyses of subunit composition and post-translational modifications of native brain proteins, and for proteomic analyses of native brain protein networks. The NeuroMab facility was initially funded with a five-year U24 cooperative grant from NINDS and NIMH. The initial goal of the facility for this funding period is to generate a library of novel NeuroMabs against neuronal proteins, initially focusing on membrane proteins (receptors/channels/transporters), synaptic proteins, other neuronal signaling molecules, and proteins with established links to disease states. The scope of the facility was expanded with supplements from the NIH Blueprint for Neuroscience Research to include neurodevelopmental targets, the NIH Roadmap for Medical Research to include epigenetics targets, and NIH Office of Rare Diseases Research to include rare disease targets. These NeuroMabs will then be produced on a large scale and made available to the neuroscience research community on an inexpensive basis as tissue culture supernatants or purified immunoglobulin by Antibodies Inc. The UC Davis/NIH NeuroMab Facility makes NeuroMabs available directly to end users and is unable to accommodate sales to distributors for third party distribution. Note, NeuroMab antibodies are now offered through antibodiesinc.
View all literature mentionsSoftware tool to help study pre-mRNA splicing and to better understand intronic and exonic mutations leading to splicing defects. To calculate the consensus values of potential splice sites and search for branch points, new algorithms were developed. Furthermore, they have integrated all available matrices to identify exonic and intronic motifs, as well as new matrices to identify hnRNP A1, Tra2-? and 9G8.
View all literature mentionsSpecific short oligonucleotide sequences that enhance pre-mRNA splicing when present in exons, termed exonic splicing enhancers (ESEs), play important roles in constitutive and alternative splicing (ESE References). A hybrid computational/experimental method, RESCUE-ESE, was recently developed for identifying sequences with ESE activity. In this approach, specific hexanucleotide sequences are identified as candidate ESEs on the basis that they have both significantly higher frequency of occurrence in exons than in introns and also significantly higher frequency in exons with weak (non-consensus) splice sites than in exons with strong (consensus) splice sites. Representative hexamers from ten different classes of candidate ESEs, together with 6 or 7 bases of flanking sequence context on each side, were introduced into a weak (poorly spliced) exon in a splicing reporter construct. These reporter minigenes were then transfected into cultured cells, where they are transcribed and spliced, and the relative level of inclusion of the test exon was assayed by quantitative (radio-labeled) RT-PCR. Point mutants of these sequences were also analyzed to confirm the precise motifs responsible for ESE activity. The RESCUE-ESE approach identified 238 hexamers as candidate ESEs using a large database of human genes of known exon-intron structure containing over 30,000 nonredudant exons. In more recent analyses by Yeo et al., the RESCUE-ESE approach was utilized to predict hexamers as candidate ESEs in other vertebrate genes, namely, Fugu rubipes, Zebrafish and Mouse. This allows the identification of motifs that are conserved in vertebrates. This web server allows a sequence to be checked for presence of these candidate ESE hexamers.
View all literature mentionsEvaluates disease-causing potential of sequence alterations.
View all literature mentionsCell line COS-7 is a Transformed cell line with a species of origin Chlorocebus aethiops (Green monkey)
View all literature mentionsCell line HEK293 is a Transformed cell line with a species of origin Homo sapiens (Human)
View all literature mentionsThe SciCrunch Infrastructure was developed as a cooperative data platform to be used by diverse communities in making data more FAIR.
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