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De novo mutations in schizophrenia implicate synaptic networks

Published on Feb 1, 2014in Nature43.07
· DOI :10.1038/nature12929
Menachem Fromer1
Estimated H-index: 1
(MIT: Massachusetts Institute of Technology),
Andrew Pocklington21
Estimated H-index: 21
+ 29 AuthorsMichael C. O’Donovan120
Estimated H-index: 120
(Cardiff University)
Cite
Abstract
Inherited alleles account for most of the genetic risk for schizophrenia. However, new (de novo) mutations, in the form of large chromosomal copy number changes, occur in a small fraction of cases and disproportionally disrupt genes encoding postsynaptic proteins. Here we show that small de novo mutations, affecting one or a few nucleotides, are overrepresented among glutamatergic postsynaptic proteins comprising activity-regulated cytoskeleton-associated protein (ARC) and N-methyl-d-aspartate receptor (NMDAR) complexes. Mutations are additionally enriched in proteins that interact with these complexes to modulate synaptic strength, namely proteins regulating actin filament dynamics and those whose messenger RNAs are targets of fragile X mental retardation protein (FMRP). Genes affected by mutations in schizophrenia overlap those mutated in autism and intellectual disability, as do mutation-enriched synaptic pathways. Aligning our findings with a parallel case–control study, we demonstrate reproducible insights into aetiological mechanisms for schizophrenia and reveal pathophysiology shared with other neurodevelopmental disorders.
  • References (44)
  • Citations (794)
Cite
References44
Newest
Published on Feb 1, 2014in Nature43.07
Shaun Purcell95
Estimated H-index: 95
,
Jennifer L. Moran40
Estimated H-index: 40
(MIT: Massachusetts Institute of Technology)
+ 29 AuthorsAnna K. Kaehler24
Estimated H-index: 24
(KI: Karolinska Institutet)
Exome sequence analysis of more than 5,000 schizophrenia cases and controls identifies a polygenic burden primarily arising from rare, disruptive mutations distributed across many genes, among which are those encoding voltage-gated calcium ion channels and the signalling complex formed by the ARC protein of the postsynaptic density; as in autism, mutations were also found in homologues of known targets of the fragile X mental retardation protein.
Published on Nov 1, 2013in Nature Neuroscience21.13
Jennifer C. Darnell21
Estimated H-index: 21
(Rockefeller University),
Eric Klann48
Estimated H-index: 48
In this review, the authors discuss the function of fragile X mental retardation protein (FMRP) in regulating the synthesis of plasticity-related target proteins. The authors review the known mRNA targets of FMRP and discuss the potential therapeutic implications of this research.
Published on Aug 1, 2013in Cell36.22
Suleyman Gulsuner15
Estimated H-index: 15
(UW: University of Washington),
Thomas J. Walsh60
Estimated H-index: 60
(UW: University of Washington)
+ 13 AuthorsRodney C.P. Go39
Estimated H-index: 39
(UAB: University of Alabama at Birmingham)
SUMMARY Genes disrupted in schizophrenia may be revealed by de novo mutations in affected persons from otherwise healthy families. Furthermore, during normal brain development, genes are expressed in patterns specifictodevelopmentalstageandneuroanatomical structure. Weidentified denovomutationsin persons with schizophrenia and then mapped the responsible genes onto transcriptome profiles of normal human brain tissues from age 13 weeks gestation to adulthood. In the dorsolateral and ventrolateral...
Published on Jul 1, 2013in Cell36.22
Jason Aoto12
Estimated H-index: 12
(Stanford University),
David C. Martinelli11
Estimated H-index: 11
(Stanford University)
+ 2 AuthorsThomas C. Südhof163
Estimated H-index: 163
(Stanford University)
Summary Neurexins are essential presynaptic cell adhesion molecules that are linked to schizophrenia and autism and are subject to extensive alternative splicing. Here, we used a genetic approach to test the physiological significance of neurexin alternative splicing. We generated knockin mice in which alternatively spliced sequence #4 (SS4) of neuexin-3 is constitutively included but can be selectively excised by cre-recombination. SS4 of neurexin-3 was chosen because it is highly regulated and...
Published on Jun 1, 2013in Neuron14.40
Takayasu Mikuni6
Estimated H-index: 6
(UTokyo: University of Tokyo),
Naofumi Uesaka12
Estimated H-index: 12
(UTokyo: University of Tokyo)
+ 4 AuthorsMasanobu Kano71
Estimated H-index: 71
(UTokyo: University of Tokyo)
Summary Neural circuits are shaped by activity-dependent elimination of redundant synapses during postnatal development. In many systems, postsynaptic activity is known to be crucial, but the precise mechanisms remain elusive. Here, we report that the immediate early gene Arc/Arg3.1 mediates elimination of surplus climbing fiber (CF) to Purkinje cell (PC) synapses in the developing cerebellum. CF synapse elimination was accelerated when activity of channelrhodopsin-2-expressing PCs was elevated ...
Published on Dec 1, 2012in Nature Genetics25.45
Bin Xu17
Estimated H-index: 17
,
Iuliana Ionita-Laza21
Estimated H-index: 21
+ 6 AuthorsMaria Karayiorgou56
Estimated H-index: 56
Maria Karayiorgou, Joseph Gogos and colleagues report exome sequencing of 231 individuals with schizophrenia and their unaffected parents. They observed an excess of de novo nonsynonymous variants among probands and identified four genes (LAMA2, DPYD, TRRAP and VPS39) altered by recurrent de novo events.
Published on Dec 1, 2012in Neuron14.40
Joseph D. Buxbaum95
Estimated H-index: 95
(ISMMS: Icahn School of Medicine at Mount Sinai),
M. J. Daly177
Estimated H-index: 177
(Harvard University)
+ 3 AuthorsMatthew W. State60
Estimated H-index: 60
(Yale University)
Research during the past decade has seen significant progress in the understanding of the genetic architecture of autism spectrum disorders (ASDs), with gene discovery accelerating as the characterization of genomic variation has become increasingly comprehensive. At the same time, this research has highlighted ongoing challenges. Here we address the enormous impact of high-throughput sequencing (HTS) on ASD gene discovery, outline a consensus view for leveraging this technology, and describe a ...
Published on Nov 15, 2012in The New England Journal of Medicine70.67
Joep de Ligt18
Estimated H-index: 18
(Radboud University Nijmegen Medical Centre),
Marjolein H. Willemsen23
Estimated H-index: 23
+ 11 AuthorsMarisol del Rosario5
Estimated H-index: 5
We evaluated patients with intellectual disability to exclude known causes of the disorder. We then sequenced the coding regions of more than 21,000 genes obtained from 100 patients with an IQ below 50 and their unaffected parents. A data-analysis procedure was developed to identify and classify de novo, autosomal recessive, and X-linked mutations. In addition, we used high-throughput resequencing to confirm new candidate genes in 765 persons with intellectual disability (a confirmation series)....
Published on Nov 10, 2012in Nucleic Acids Research11.15
Joachim von Eichborn6
Estimated H-index: 6
,
Mathias Dunkel18
Estimated H-index: 18
+ 12 AuthorsNicolas Le Novère53
Estimated H-index: 53
We created SynSysNet, available online at http://bioinformatics.charite.de/ synsysnet, to provide a platform that creates a comprehensive 4D network of synaptic interactions. Neuronal synapses are fundamental structures linking nerve cells in the brain and they are responsible for neuronal communication and information processing. These processes are dynamically regulated by a network of proteins. New developments in interaction prote-omics and yeast two-hybrid methods allow unbiased detection o...
Published on Nov 1, 2012in The Lancet59.10
Anita Rauch55
Estimated H-index: 55
,
Dagmar Wieczorek47
Estimated H-index: 47
+ 36 AuthorsNataliya Di Donato13
Estimated H-index: 13
(TUD: Dresden University of Technology)
Summary Background The genetic cause of intellectual disability in most patients is unclear because of the absence of morphological clues, information about the position of such genes, and suitable screening methods. Our aim was to identify de-novo variants in individuals with sporadic non-syndromic intellectual disability. Methods In this study, we enrolled children with intellectual disability and their parents from ten centres in Germany and Switzerland. We compared exome sequences between pa...
Cited By794
Newest
Published on 2019in Nature Communications11.88
David J. Kast11
Estimated H-index: 11
(UPenn: University of Pennsylvania),
Roberto Dominguez37
Estimated H-index: 37
(UPenn: University of Pennsylvania)
Filopodia are precursors of dendritic spines and polarized cell migration. The I-BAR-domain protein IRSp53 is a key regulator of filopodia dynamics that couples Rho-GTPase signaling to cytoskeleton and membrane remodeling, playing essential roles in neuronal development and cell motility. Here, we describe the structural-functional basis for 14-3-3-dependent inhibition of IRSp53. Phosphoproteomics, quantitative binding and crystallographic studies demonstrate that 14-3-3 binds to two pairs of ph...
Published on Dec 1, 2019in Translational Psychiatry5.18
Hengyi Cao6
Estimated H-index: 6
(Yale University),
Martin Ingvar63
Estimated H-index: 63
(KI: Karolinska Institutet)
+ 1 AuthorsTyrone D. Cannon87
Estimated H-index: 87
(Yale University)
Our recent study has demonstrated that increased connectivity in the cerebello-thalamo-cortical (CTC) circuitry is a state-independent neural trait that can potentially predict the onset of psychosis. One possible cause of such “trait” abnormality would be genetic predisposition. Here, we tested this hypothesis using multi-paradigm functional magnetic resonance imaging (fMRI) data from two independent twin cohorts. In a sample of 85 monozygotic (MZ) and 52 dizygotic (DZ) healthy twin pairs acqui...
Published on 2019in Nature Communications11.88
Stephan C. Collins19
Estimated H-index: 19
,
Anna Mikhaleva1
Estimated H-index: 1
(UNIL: University of Lausanne)
+ 7 AuthorsLauren F. E. Anthony
Brain morphogenesis is an important process contributing to higher-order cognition, however our knowledge about its biological basis is largely incomplete. Here we analyze 118 neuroanatomical parameters in 1,566 mutant mouse lines and identify 198 genes whose disruptions yield NeuroAnatomical Phenotypes (NAPs), mostly affecting structures implicated in brain connectivity. Groups of functionally similar NAP genes participate in pathways involving the cytoskeleton, the cell cycle and the synapse, ...
Betina Elfving21
Estimated H-index: 21
(AU: Aarhus University),
Heidi Kaastrup Müller13
Estimated H-index: 13
(AU: Aarhus University)
+ 6 AuthorsSusana Aznar21
Estimated H-index: 21
Abstract Schizophrenia is considered a neurodevelopmental disorder. Recent reports relate synaptic alterations with disease etiology. The inbred Roman High- (RHA-I) and Low- (RLA-I) Avoidance rat strains are a congenital neurobehavioral model, with the RHA-I displaying schizophrenia-related behaviors and serotonin 2A (5-HT2A) and metabotropic glutamate 2 (mGlu2) receptor alterations in the prefrontal cortex (PFC). We performed a comprehensive characterization of the RHA-I/RLA-I rats by real-time...
Published on 2019in Scientific Data
Gabriel Hoffman14
Estimated H-index: 14
(ISMMS: Icahn School of Medicine at Mount Sinai),
Jaroslav Bendl2
Estimated H-index: 2
(ISMMS: Icahn School of Medicine at Mount Sinai)
+ 7 AuthorsKiran Girdhar4
Estimated H-index: 4
(ISMMS: Icahn School of Medicine at Mount Sinai)
Schizophrenia and bipolar disorder are serious mental illnesses that affect more than 2% of adults. While large-scale genetics studies have identified genomic regions associated with disease risk, less is known about the molecular mechanisms by which risk alleles with small effects lead to schizophrenia and bipolar disorder. In order to fill this gap between genetics and disease phenotype, we have undertaken a multi-cohort genomics study of postmortem brains from controls, individuals with schiz...
Published on Dec 1, 2019
Rebecca A. DeGiosio1
Estimated H-index: 1
(University of Pittsburgh),
Ryan M. Kelly1
Estimated H-index: 1
(University of Pittsburgh)
+ 5 AuthorsRobert A. Sweet53
Estimated H-index: 53
(University of Pittsburgh)
Several postmortem studies have reported lower levels of immunoreactivity (IR) for microtubule-associated protein 2 (MAP2) in several cortical regions of individuals with schizophrenia (SZ). However, whether this effect is conserved across multiple brain areas within an individual with SZ or if it is regionally-specific remains unclear. We characterized patterns of MAP2-IR across three cortical regions at different levels of the rostral-caudal axis within individual subjects with and without SZ....
Published on Mar 28, 2019in Molecular Autism5.71
Tetsuya Tatsukawa3
Estimated H-index: 3
,
Tetsuya Tatsukawa4
Estimated H-index: 4
+ 7 AuthorsTsuyoshi Miyakawa49
Estimated H-index: 49
(Fujita Health University)
Background Mutations of the SCN2A gene encoding a voltage-gated sodium channel alpha-II subunit Nav1.2 are associated with neurological disorders such as epilepsy, autism spectrum disorders, intellectual disability, and schizophrenia. However, causal relationships and pathogenic mechanisms underlying these neurological defects, especially social and psychiatric features, remain to be elucidated.
Published on Dec 1, 2019in Nature Communications11.88
Hyejung Won21
Estimated H-index: 21
(UNC: University of North Carolina at Chapel Hill),
Jerry Huang2
Estimated H-index: 2
(UCLA: University of California, Los Angeles)
+ 2 AuthorsDaniel H. Geschwind122
Estimated H-index: 122
(UCLA: University of California, Los Angeles)
Modern genetic studies indicate that human brain evolution is driven primarily by changes in gene regulation, which requires understanding the biological function of largely non-coding gene regulatory elements, many of which act in tissue specific manner. We leverage chromatin interaction profiles in human fetal and adult cortex to assign three classes of human-evolved elements to putative target genes. We find that human-evolved elements involving DNA sequence changes and those involving epigen...
Published on Dec 1, 2019in Translational Psychiatry5.18
Zhonghua Hu7
Estimated H-index: 7
(NIH: National Institutes of Health),
Shuoguo Gao (NIH: National Institutes of Health)+ 6 AuthorsZheng Li19
Estimated H-index: 19
(NIH: National Institutes of Health)
Brain development is dependent on programmed gene expression, which is both genetically and epigenetically regulated. Post-transcriptional regulation of gene expression by microRNAs (miRNAs) is essential for brain development. As abnormal brain development is hypothesized to be associated with schizophrenia, miRNAs are an intriguing target for this disorder. The aims of this study were to determine the temporal dynamics of miRNA expression in the human dorsolateral prefrontal cortex (DLPFC), and...
Abstract DISC1 was discovered as a gene disrupted by a balanced translocation in a large pedigree that segregated with major mental disorders, including schizophrenia. Further attempts to find genetic association with schizophrenia were inconclusive. Most of the biology of DISC1 was inferred from the functionality of its protein partners. Recently, a gene set constituted by DISC1 and several of its partners has been associated with cognitive performance during development, a well-known schizophr...
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