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Journal ArticleDOI

FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism

TL;DR: A brain polyribosome-programmed translation system is developed, revealing that FMRP reversibly stalls ribosomes specifically on its target mRNAs and suggests multiple targets for clinical intervention in FXS and ASD.
About: This article is published in Cell.The article was published on 2011-07-22 and is currently open access. It has received 1861 citations till now. The article focuses on the topics: FMR1 & RNA-binding protein.
Citations
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Journal ArticleDOI
Silvia De Rubeis1, Xin-Xin He2, Arthur P. Goldberg1, Christopher S. Poultney1, Kaitlin E. Samocha3, A. Ercument Cicek2, Yan Kou1, Li Liu2, Menachem Fromer3, Menachem Fromer1, R. Susan Walker4, Tarjinder Singh5, Lambertus Klei6, Jack A. Kosmicki3, Shih-Chen Fu1, Branko Aleksic7, Monica Biscaldi8, Patrick Bolton9, Jessica M. Brownfeld1, Jinlu Cai1, Nicholas G. Campbell10, Angel Carracedo11, Angel Carracedo12, Maria H. Chahrour3, Andreas G. Chiocchetti, Hilary Coon13, Emily L. Crawford10, Lucy Crooks5, Sarah Curran9, Geraldine Dawson14, Eftichia Duketis, Bridget A. Fernandez15, Louise Gallagher16, Evan T. Geller17, Stephen J. Guter18, R. Sean Hill19, R. Sean Hill3, Iuliana Ionita-Laza20, Patricia Jiménez González, Helena Kilpinen, Sabine M. Klauck21, Alexander Kolevzon1, Irene Lee22, Jing Lei2, Terho Lehtimäki, Chiao-Feng Lin17, Avi Ma'ayan1, Christian R. Marshall4, Alison L. McInnes23, Benjamin M. Neale24, Michael John Owen25, Norio Ozaki7, Mara Parellada26, Jeremy R. Parr27, Shaun Purcell1, Kaija Puura, Deepthi Rajagopalan4, Karola Rehnström5, Abraham Reichenberg1, Aniko Sabo28, Michael Sachse, Stephen Sanders29, Chad M. Schafer2, Martin Schulte-Rüther30, David Skuse31, David Skuse22, Christine Stevens24, Peter Szatmari32, Kristiina Tammimies4, Otto Valladares17, Annette Voran33, Li-San Wang17, Lauren A. Weiss29, A. Jeremy Willsey29, Timothy W. Yu3, Timothy W. Yu19, Ryan K. C. Yuen4, Edwin H. Cook18, Christine M. Freitag, Michael Gill16, Christina M. Hultman34, Thomas Lehner35, Aarno Palotie3, Aarno Palotie24, Aarno Palotie36, Gerard D. Schellenberg17, Pamela Sklar1, Matthew W. State29, James S. Sutcliffe10, Christopher A. Walsh19, Christopher A. Walsh3, Stephen W. Scherer4, Michael E. Zwick37, Jeffrey C. Barrett5, David J. Cutler37, Kathryn Roeder2, Bernie Devlin6, Mark J. Daly3, Mark J. Daly24, Joseph D. Buxbaum1 
13 Nov 2014-Nature
TL;DR: Using exome sequencing, it is shown that analysis of rare coding variation in 3,871 autism cases and 9,937 ancestry-matched or parental controls implicates 22 autosomal genes at a false discovery rate of < 0.05, plus a set of 107 genes strongly enriched for those likely to affect risk (FDR < 0.30).
Abstract: The genetic architecture of autism spectrum disorder involves the interplay of common and rare variants and their impact on hundreds of genes. Using exome sequencing, here we show that analysis of rare coding variation in 3,871 autism cases and 9,937 ancestry-matched or parental controls implicates 22 autosomal genes at a false discovery rate (FDR) < 0.05, plus a set of 107 autosomal genes strongly enriched for those likely to affect risk (FDR < 0.30). These 107 genes, which show unusual evolutionary constraint against mutations, incur de novo loss-of-function mutations in over 5% of autistic subjects. Many of the genes implicated encode proteins for synaptic formation, transcriptional regulation and chromatin-remodelling pathways. These include voltage-gated ion channels regulating the propagation of action potentials, pacemaking and excitability-transcription coupling, as well as histone-modifying enzymes and chromatin remodellers-most prominently those that mediate post-translational lysine methylation/demethylation modifications of histones.

2,228 citations

Journal ArticleDOI
13 Nov 2014-Nature
TL;DR: It is estimated that LGD mutation in about 400 genes can contribute to the joint class of affected females and males of lower IQ, with an overlapping and similar number of genes vulnerable to contributory missense mutation.
Abstract: Whole exome sequencing has proven to be a powerful tool for understanding the genetic architecture of human disease. Here we apply it to more than 2,500 simplex families, each having a child with an autistic spectrum disorder. By comparing affected to unaffected siblings, we show that 13% of de novo missense mutations and 43% of de novo likely gene-disrupting (LGD) mutations contribute to 12% and 9% of diagnoses, respectively. Including copy number variants, coding de novo mutations contribute to about 30% of all simplex and 45% of female diagnoses. Almost all LGD mutations occur opposite wild-type alleles. LGD targets in affected females significantly overlap the targets in males of lower intelligence quotient (IQ), but neither overlaps significantly with targets in males of higher IQ. We estimate that LGD mutation in about 400 genes can contribute to the joint class of affected females and males of lower IQ, with an overlapping and similar number of genes vulnerable to contributory missense mutation. LGD targets in the joint class overlap with published targets for intellectual disability and schizophrenia, and are enriched for chromatin modifiers, FMRP-associated genes and embryonically expressed genes. Most of the significance for the latter comes from affected females.

2,124 citations

Journal ArticleDOI
11 Nov 2011-Cell
TL;DR: A suite of techniques, based on ribosome profiling, are presented to provide genome-wide maps of protein synthesis as well as a pulse-chase strategy for determining rates of translation elongation, revealing an unanticipated complexity to mammalian proteomes.

1,953 citations


Cites background from "FMRP stalls ribosomal translocation..."

  • ...We also know that the rate of translation is not constant across a message, and translation pauses can regulate synthesis (Darnell et al., 2011; Morris and Geballe, 2000), folding (Kimchi-Sarfaty et al., 2007; Zhang et al., 2009), and localization of a protein (Mariappan et al., 2010) or mRNA…...

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Journal ArticleDOI
13 Feb 2014-Nature
TL;DR: Genes affected by mutations in schizophrenia overlap those mutated in autism and intellectual disability, as do mutation-enriched synaptic pathways, and pathophysiology shared with other neurodevelopmental disorders.
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.

1,501 citations

Journal ArticleDOI
26 Apr 2012-Neuron
TL;DR: Exome sequencing of 343 families, each with a single child on the autism spectrum and at least one unaffected sibling, reveals de novo small indels and point substitutions, which suggest FMRP-associated genes are especially dosage-sensitive targets of cognitive disorders.

1,354 citations


Cites background from "FMRP stalls ribosomal translocation..."

  • ...This has suggested overlaying recent understanding of FXS biology onto candidate ASD genes (Darnell et al., 2011)....

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  • ...We observe an unusual coincidence between the list of genes with disruptive de novo mutations in children with autism and the list of 842 gene products associated with FMRP (Darnell et al., 2011), itself a target of mutation in 2% of children with ASD....

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  • ...Mediators of Neuroplasticity inCognitive andBehavioral Disorders FMRP may act as one component of a central regulator of synaptic plasticity, among others such as TSC2 (Darnell et al., 2011; Auerbach et al., 2011)....

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  • ...Significant overlap of the 842 FMRP-associated genes with autism candidate genes has been previously suggested (Darnell et al., 2011)....

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  • ...Other de novo mutations of interest were a 4 bp deletion in DST (encoding the basement membrane glycoprotein dystonin), which is associated with FMRP (Darnell et al., 2011) and produces a neurodegeneration phenotype when inactivated in themouse, and a nonsensemutation in ANK2 (an ankyrin protein involved in synaptic stability [Koch et al....

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References
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Journal ArticleDOI
TL;DR: In this paper, a different approach to problems of multiple significance testing is presented, which calls for controlling the expected proportion of falsely rejected hypotheses -the false discovery rate, which is equivalent to the FWER when all hypotheses are true but is smaller otherwise.
Abstract: SUMMARY The common approach to the multiplicity problem calls for controlling the familywise error rate (FWER). This approach, though, has faults, and we point out a few. A different approach to problems of multiple significance testing is presented. It calls for controlling the expected proportion of falsely rejected hypotheses -the false discovery rate. This error rate is equivalent to the FWER when all hypotheses are true but is smaller otherwise. Therefore, in problems where the control of the false discovery rate rather than that of the FWER is desired, there is potential for a gain in power. A simple sequential Bonferronitype procedure is proved to control the false discovery rate for independent test statistics, and a simulation study shows that the gain in power is substantial. The use of the new procedure and the appropriateness of the criterion are illustrated with examples.

83,420 citations


"FMRP stalls ribosomal translocation..." refers methods in this paper

  • ...False discovery rate (FDR) was estimated by the Benjamini-Hochberg method (Benjamini and Hochberg, 1995)....

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  • ...p-values reported for this study were corrected using the Benjamini-Hochberg approach (Benjamini and Hochberg, 1995)....

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Journal ArticleDOI
TL;DR: By following this protocol, investigators are able to gain an in-depth understanding of the biological themes in lists of genes that are enriched in genome-scale studies.
Abstract: DAVID bioinformatics resources consists of an integrated biological knowledgebase and analytic tools aimed at systematically extracting biological meaning from large gene/protein lists. This protocol explains how to use DAVID, a high-throughput and integrated data-mining environment, to analyze gene lists derived from high-throughput genomic experiments. The procedure first requires uploading a gene list containing any number of common gene identifiers followed by analysis using one or more text and pathway-mining tools such as gene functional classification, functional annotation chart or clustering and functional annotation table. By following this protocol, investigators are able to gain an in-depth understanding of the biological themes in lists of genes that are enriched in genome-scale studies.

31,015 citations


"FMRP stalls ribosomal translocation..." refers methods in this paper

  • ...We used the DAVID Bioinformatics database to analyze the gene ontology (GO) terms assigned to them....

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  • ...Gene Ontology Analysis The enrichment of gene ontology (GO) terms in FMRP targets was analyzed using the online tool DAVID (Huang et al., 2009; Dennis et al., 2003)....

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  • ...GO functional category enrichment was analyzed using DAVID 6.7 software....

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TL;DR: In this paper, the authors present a model for the analysis of variance in a single-classification and two-way and multiway analysis of Variance with the assumption of correlation.
Abstract: 1. Introduction 2. Data in Biology 3. Computers and Data Analysis 4. Descriptive Statistics 5. Introduction to Probability Distributions 6. The Normal Probability Distribution 7. Hypothesis Testing and Interval Estimation 8. Introduction to Analysis of Variance 9. Single-Classification Analysis of Variance 10. Nested Analysis of Variance 11. Two-Way and Multiway Analysis of Variance 12. Statistical Power and Sample Size in the Analysis of Variance 13. Assumptions of Analysis of Variance 14. Linear Regression 15. Correlation 16. Multiple and Curvilinear Regression 17. Analysis of Frequencies 18. Meta-Analysis and Miscellaneous Methods

23,447 citations

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TL;DR: In this paper, the authors present a model for the analysis of variance in a single-classification and two-way and multiway analysis of Variance with the assumption of correlation.
Abstract: 1. Introduction 2. Data in Biology 3. Computers and Data Analysis 4. Descriptive Statistics 5. Introduction to Probability Distributions 6. The Normal Probability Distribution 7. Hypothesis Testing and Interval Estimation 8. Introduction to Analysis of Variance 9. Single-Classification Analysis of Variance 10. Nested Analysis of Variance 11. Two-Way and Multiway Analysis of Variance 12. Statistical Power and Sample Size in the Analysis of Variance 13. Assumptions of Analysis of Variance 14. Linear Regression 15. Correlation 16. Multiple and Curvilinear Regression 17. Analysis of Frequencies 18. Meta-Analysis and Miscellaneous Methods

21,276 citations

Journal ArticleDOI
TL;DR: The hierarchical model of Lonnstedt and Speed (2002) is developed into a practical approach for general microarray experiments with arbitrary numbers of treatments and RNA samples and the moderated t-statistic is shown to follow a t-distribution with augmented degrees of freedom.
Abstract: The problem of identifying differentially expressed genes in designed microarray experiments is considered. Lonnstedt and Speed (2002) derived an expression for the posterior odds of differential expression in a replicated two-color experiment using a simple hierarchical parametric model. The purpose of this paper is to develop the hierarchical model of Lonnstedt and Speed (2002) into a practical approach for general microarray experiments with arbitrary numbers of treatments and RNA samples. The model is reset in the context of general linear models with arbitrary coefficients and contrasts of interest. The approach applies equally well to both single channel and two color microarray experiments. Consistent, closed form estimators are derived for the hyperparameters in the model. The estimators proposed have robust behavior even for small numbers of arrays and allow for incomplete data arising from spot filtering or spot quality weights. The posterior odds statistic is reformulated in terms of a moderated t-statistic in which posterior residual standard deviations are used in place of ordinary standard deviations. The empirical Bayes approach is equivalent to shrinkage of the estimated sample variances towards a pooled estimate, resulting in far more stable inference when the number of arrays is small. The use of moderated t-statistics has the advantage over the posterior odds that the number of hyperparameters which need to estimated is reduced; in particular, knowledge of the non-null prior for the fold changes are not required. The moderated t-statistic is shown to follow a t-distribution with augmented degrees of freedom. The moderated t inferential approach extends to accommodate tests of composite null hypotheses through the use of moderated F-statistics. The performance of the methods is demonstrated in a simulation study. Results are presented for two publicly available data sets.

11,864 citations


"FMRP stalls ribosomal translocation..." refers methods in this paper

  • ...Differential expression between wild-type or FMRP knockout brains was evaluated by the naive Bayes method, using total RNA level or normalized polysome RNA level (Smyth, 2004)....

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