Author
Ingo H. Greger
Other affiliations: Howard Hughes Medical Institute, University of Cambridge, New York University
Bio: Ingo H. Greger is an academic researcher from Laboratory of Molecular Biology. The author has contributed to research in topics: AMPA receptor & Neurotransmission. The author has an hindex of 27, co-authored 45 publications receiving 2886 citations. Previous affiliations of Ingo H. Greger include Howard Hughes Medical Institute & University of Cambridge.
Papers
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TL;DR: It is shown that the functionally critical GluR2 subunit stably resides in an intracellular pool in the endoplasmic reticulum (ER) and that Arg607 is a central regulator that controls ER exit and may thereby ensure the availability of GLUR2 for assembly into AMPARs.
353 citations
National Institute for Health Research1, Wellcome Trust Centre for Human Genetics2, University of Oxford3, Illumina4, University of Coimbra5, Laboratory of Molecular Biology6, University of Ulm7, Cliniques Universitaires Saint-Luc8, University of Zurich9, University Hospital Southampton NHS Foundation Trust10, Northwestern University11, Queen's University Belfast12, Imperial College London13, Copenhagen University Hospital14, Belfast City Hospital15, King's College London16, Shriners Hospitals for Children17
TL;DR: It is found that jointly calling variants across samples, filtering against both local and external databases, deploying multiple annotation tools and using familial transmission above biological plausibility contributed to accuracy.
Abstract: To assess factors influencing the success of whole-genome sequencing for mainstream clinical diagnosis, we sequenced 217 individuals from 156 independent cases or families across a broad spectrum of disorders in whom previous screening had identified no pathogenic variants. We quantified the number of candidate variants identified using different strategies for variant calling, filtering, annotation and prioritization. We found that jointly calling variants across samples, filtering against both local and external databases, deploying multiple annotation tools and using familial transmission above biological plausibility contributed to accuracy. Overall, we identified disease-causing variants in 21% of cases, with the proportion increasing to 34% (23/68) for mendelian disorders and 57% (8/14) in family trios. We also discovered 32 potentially clinically actionable variants in 18 genes unrelated to the referral disorder, although only 4 were ultimately considered reportable. Our results demonstrate the value of genome sequencing for routine clinical diagnosis but also highlight many outstanding challenges.
318 citations
TL;DR: It is demonstrated that editing at the GluR2 Q/R site regulates AMPAR assembly at the step of tetramerization, and a single amino acid residue affects channel composition and, in turn, controls ion conduction through the majority of AMPARs in the brain.
311 citations
TL;DR: How the subunit structure, stoichiometry, and auxiliary subunits generate a heterogeneous plethora of receptors, each tailored to fulfill a vital role in fast synaptic signaling and plasticity are discussed.
252 citations
TL;DR: Progress has been made in understanding the molecular mechanisms underlying subunit assembly and receptor biogenesis in the ER, which determine the size and shape of the postsynaptic response, and are the subject of this review.
187 citations
Cited by
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Journal Article•
28,685 citations
TL;DR: This review discusses International Union of Basic and Clinical Pharmacology glutamate receptor nomenclature, structure, assembly, accessory subunits, interacting proteins, gene expression and translation, post-translational modifications, agonist and antagonist pharmacology, allosteric modulation, mechanisms of gating and permeation, roles in normal physiological function, as well as the potential therapeutic use of pharmacological agents acting at glutamate receptors.
Abstract: The mammalian ionotropic glutamate receptor family encodes 18 gene products that coassemble to form ligand-gated ion channels containing an agonist recognition site, a transmembrane ion permeation pathway, and gating elements that couple agonist-induced conformational changes to the opening or closing of the permeation pore. Glutamate receptors mediate fast excitatory synaptic transmission in the central nervous system and are localized on neuronal and non-neuronal cells. These receptors regulate a broad spectrum of processes in the brain, spinal cord, retina, and peripheral nervous system. Glutamate receptors are postulated to play important roles in numerous neurological diseases and have attracted intense scrutiny. The description of glutamate receptor structure, including its transmembrane elements, reveals a complex assembly of multiple semiautonomous extracellular domains linked to a pore-forming element with striking resemblance to an inverted potassium channel. In this review we discuss International Union of Basic and Clinical Pharmacology glutamate receptor nomenclature, structure, assembly, accessory subunits, interacting proteins, gene expression and translation, post-translational modifications, agonist and antagonist pharmacology, allosteric modulation, mechanisms of gating and permeation, roles in normal physiological function, as well as the potential therapeutic use of pharmacological agents acting at glutamate receptors.
3,044 citations
01 Jan 2011
TL;DR: The sheer volume and scope of data posed by this flood of data pose a significant challenge to the development of efficient and intuitive visualization tools able to scale to very large data sets and to flexibly integrate multiple data types, including clinical data.
Abstract: Rapid improvements in sequencing and array-based platforms are resulting in a flood of diverse genome-wide data, including data from exome and whole-genome sequencing, epigenetic surveys, expression profiling of coding and noncoding RNAs, single nucleotide polymorphism (SNP) and copy number profiling, and functional assays. Analysis of these large, diverse data sets holds the promise of a more comprehensive understanding of the genome and its relation to human disease. Experienced and knowledgeable human review is an essential component of this process, complementing computational approaches. This calls for efficient and intuitive visualization tools able to scale to very large data sets and to flexibly integrate multiple data types, including clinical data. However, the sheer volume and scope of data pose a significant challenge to the development of such tools.
2,187 citations
University of Minnesota1, University of Colorado Boulder2, VU University Amsterdam3, Harvard University4, University of Southern California5, University of Tartu6, University of Queensland7, Erasmus University Rotterdam8, Hospital for Special Surgery9, University of Copenhagen10, Statens Serum Institut11, Broad Institute12, University of Essex13, University of Edinburgh14, University of Cambridge15, University Hospital of Lausanne16, Geisinger Health System17, Wenzhou Medical College18, Stanford University19, University of North Carolina at Chapel Hill20, University of Wisconsin-Madison21, The Feinstein Institute for Medical Research22, Hofstra University23, University of Dundee24, University of Toronto25, Princeton University26, National Bureau of Economic Research27, New York University Shanghai28, Queen's University29, Karolinska Institutet30, Uppsala University31, University of Lausanne32, New York University33, Stockholm School of Economics34
TL;DR: A joint (multi-phenotype) analysis of educational attainment and three related cognitive phenotypes generates polygenic scores that explain 11–13% of the variance ineducational attainment and 7–10% ofthe variance in cognitive performance, which substantially increases the utility ofpolygenic scores as tools in research.
Abstract: Here we conducted a large-scale genetic association analysis of educational attainment in a sample of approximately 1.1 million individuals and identify 1,271 independent genome-wide-significant SNPs. For the SNPs taken together, we found evidence of heterogeneous effects across environments. The SNPs implicate genes involved in brain-development processes and neuron-to-neuron communication. In a separate analysis of the X chromosome, we identify 10 independent genome-wide-significant SNPs and estimate a SNP heritability of around 0.3% in both men and women, consistent with partial dosage compensation. A joint (multi-phenotype) analysis of educational attainment and three related cognitive phenotypes generates polygenic scores that explain 11-13% of the variance in educational attainment and 7-10% of the variance in cognitive performance. This prediction accuracy substantially increases the utility of polygenic scores as tools in research.
1,658 citations
TL;DR: Current evidence suggests that neurons detect changes in their own firing rates through a set of calcium-dependent sensors that then regulate receptor trafficking to increase or decrease the accumulation of glutamate receptors at synaptic sites.
1,376 citations