G2Cdb::Gene report

Gene id
Gene symbol
Homo sapiens
glutamate receptor, metabotropic 2
G00001238 (Mus musculus)

Databases (7)

ENSG00000164082 (Ensembl human gene)
2912 (Entrez Gene)
279 (G2Cdb plasticity & disease)
GRM2 (GeneCards)
604099 (OMIM)
Marker Symbol
HGNC:4594 (HGNC)
Protein Sequence
Q14416 (UniProt)

Synonyms (3)

  • GPRC1B
  • MGLUR2
  • mGlu2

Literature (27)

Pubmed - other

  • Identification of neuroglycan C and interacting partners as potential susceptibility genes for schizophrenia in a Southern Chinese population.

    So HC, Fong PY, Chen RY, Hui TC, Ng MY, Cherny SS, Mak WW, Cheung EF, Chan RC, Chen EY, Li T and Sham PC

    Department of Psychiatry, University of Hong Kong, Hong Kong SAR, China.

    Chromosome 3p was reported by previous studies as one of the regions showing strong evidence of linkage with schizophrenia. We performed a fine-mapping association study of a 6-Mb high-LD and gene-rich region on 3p in a Southern Chinese sample of 489 schizophrenia patients and 519 controls to search for susceptibility genes. In the initial screen, 4 SNPs out of the 144 tag SNPs genotyped were nominally significant (P < 0.05). One of the most significant SNPs (rs3732530, P = 0.0048) was a non-synonymous SNP in the neuroglycan C (NGC, also known as CSPG5) gene, which belongs to the neuregulin family. The gene prioritization program Endeavor ranked NGC 8th out of the 129 genes in the 6-Mb region and the highest among the genes within the same LD block. Further genotyping of NGC revealed 3 more SNPs to be nominally associated with schizophrenia. Three other genes (NRG1, ErbB3, ErbB4) involved in the neuregulin pathways were subsequently genotyped. Interaction analysis by multifactor dimensionality reduction (MDR) revealed a significant two-SNP interaction between NGC and NRG1 (P = 0.015) and three-SNP interactions between NRG1 and ErbB4 (P = 0.009). The gene NGC is exclusively expressed in the brain. It is implicated in neurodevelopment in rats and was previously shown to promote neurite outgrowth. Methamphetamine, a drug that may induce psychotic symptoms, was reported to alter the expression of NGC. Taken together, these results suggest that NGC may be a novel candidate gene, and neuregulin signaling pathways may play an important role in schizophrenia.

    American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2010;153B;1;103-13

  • Disruption of glutamate receptors at Shank-postsynaptic platform in Alzheimer's disease.

    Gong Y, Lippa CF, Zhu J, Lin Q and Rosso AL

    Department of Neurology, Drexel University College of Medicine, 245 N 15th Street, Philadelphia, PA 19102, USA. Yuesong.Gong@drexelmed.edu

    Synaptic loss underlies the memory deficit of Alzheimer's disease (AD). The molecular mechanism is elusive; however, excitatory synapses organized by the postsynaptic density (PSD) have been used as targets for AD treatment. To identify pathological entities at the synapse in AD, synaptic proteins were screened by quantitative proteomic profiling. The critical proteins were then selected for immunoblot analysis. The glutamate receptors N-methyl-d-aspartate (NMDA) receptor 1 and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor 2 (GluR2) were substantially lost; specifically, the loss of GluR2 was up to 40% at PSD in AD. Shank proteins, the organizers of these glutamate receptors at excitatory synapses, were dramatically altered in AD. The level of Shank2 was increased, whereas the protein level of Shank3 was decreased. Further, the Shank3 protein was modified by ubiquitin, indicating that abnormal activity of the ubiquitin-proteasome system may lead to Shank3 degradation in AD. Our findings suggest that disruption of glutamate receptors at the Shank-postsynaptic platform could contribute to destruction of the PSD which underlies the synaptic dysfunction and loss in AD.

    Funded by: NCRR NIH HHS: 1S10RR01782-01A1; NIA NIH HHS: 1R21AG031388, R21 AG031388, R21 AG031388-01

    Brain research 2009;1292;191-8

  • Identification of new putative susceptibility genes for several psychiatric disorders by association analysis of regulatory and non-synonymous SNPs of 306 genes involved in neurotransmission and neurodevelopment.

    Gratacòs M, Costas J, de Cid R, Bayés M, González JR, Baca-García E, de Diego Y, Fernández-Aranda F, Fernández-Piqueras J, Guitart M, Martín-Santos R, Martorell L, Menchón JM, Roca M, Sáiz-Ruiz J, Sanjuán J, Torrens M, Urretavizcaya M, Valero J, Vilella E, Estivill X, Carracedo A and Psychiatric Genetics Network Group

    CIBER en Epidemiología y Salud Pública (CIBERESP), Instituto de Salud Carlos III, Madrid, Spain.

    A fundamental difficulty in human genetics research is the identification of the spectrum of genetic variants that contribute to the susceptibility to common/complex disorders. We tested here the hypothesis that functional genetic variants may confer susceptibility to several related common disorders. We analyzed five main psychiatric diagnostic categories (substance-abuse, anxiety, eating, psychotic, and mood disorders) and two different control groups, representing a total of 3,214 samples, for 748 promoter and non-synonymous single nucleotide polymorphisms (SNPs) at 306 genes involved in neurotransmission and/or neurodevelopment. We identified strong associations to individual disorders, such as growth hormone releasing hormone (GHRH) with anxiety disorders, prolactin regulatory element (PREB) with eating disorders, ionotropic kainate glutamate receptor 5 (GRIK5) with bipolar disorder and several SNPs associated to several disorders, that may represent individual and related disease susceptibility factors. Remarkably, a functional SNP, rs945032, located in the promoter region of the bradykinin receptor B2 gene (BDKRB2) was associated to three disorders (panic disorder, substance abuse, and bipolar disorder), and two additional BDKRB2 SNPs to obsessive-compulsive disorder and major depression, providing evidence for common variants of susceptibility to several related psychiatric disorders. The association of BDKRB2 (odd ratios between 1.65 and 3.06) to several psychiatric disorders supports the view that a common genetic variant could confer susceptibility to clinically related phenotypes, and defines a new functional hint in the pathophysiology of psychiatric diseases.

    American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2009;150B;6;808-16

  • Association analysis of group II metabotropic glutamate receptor genes (GRM2 and GRM3) with mood disorders and fluvoxamine response in a Japanese population.

    Tsunoka T, Kishi T, Ikeda M, Kitajima T, Yamanouchi Y, Kinoshita Y, Kawashima K, Okochi T, Okumura T, Inada T, Ozaki N and Iwata N

    Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi, 470-1192, Japan.

    Background: Several lines of evidence implicate abnormalities in glutamate neural transmission in the pathophysiology of mood disorders, including major depressive disorder (MDD) and bipolar disorder (BP). Preclinical antidepressant effects were also reported for group II metabotropic glutamate receptor (Group II mGluRs) antagonists show dose-dependent antidepressant-like effects in murine models of depression. Also, it has been suggested that abnormalities in the hypothalamic-pituitary-adrenal axis and serotonergic neural transmission are important mechanisms in the pathophysiology of mood disorders. Group II mGluRs play an important role in regulating the function of these mechanisms. From these results, it has been suggested that abnormalities in Group II mGluRs might be involved in the pathophysiology of mood disorders, including MDD) and BP, and may influence the clinical response to treatment with SSRIs in MDD. Therefore, we studied the association between Group II mGluR genes (GRM2 and GRM3) and mood disorders and the efficacy of fluvoxamine treatment in Japanese MDD patients.

    Using three tagging SNPs in GRM2 and an SNP (rs6465084) reported functional variant in GRM3, we conducted a genetic association analysis of case-control samples (325 MDD patients, 155 BP patients and 802 controls) in the Japanese population. In addition, we performed an association analysis of GRM2 and GRM3 and the efficacy of fluvoxamine treatment in 117 Japanese patients with MDD. The MDD patients in this study had scores of 12 or higher on the 17 items of the Structured Interview Guide for Hamilton Rating Scale for Depression (SIGH-D). We defined a clinical response as a decrease of more than 50% in baseline SIGH-D within 8 weeks, and clinical remission as an SIGH-D score of less than 7 at 8 weeks.

    Results: We found an association between rs6465084 in GRM3 and MDD in the allele-wise analysis after Bonferroni's correction (P-value=0.0371). However, we did not find any association between GRM3 and BP or the fluvoxamine therapeutic response in MDD in the allele/genotype-wise analysis. We also did not detect any association between GRM2 and MDD, BP or the fluvoxamine therapeutic response in MDD in the allele/genotype-wise or haplotype-wise analysis.

    Discussion: We detected an association between only one marker (rs6465084) in GRM3 and Japanese MDD patients. However, because we did not perform an association analysis based on LD and a mutation scan of GRM3, a replication study using a larger sample and based on LD may be required for conclusive results.

    Progress in neuro-psychopharmacology & biological psychiatry 2009;33;5;875-9

  • Mutagenesis and molecular modeling of the orthosteric binding site of the mGlu2 receptor determining interactions of the group II receptor antagonist (3)H-HYDIA.

    Lundström L, Kuhn B, Beck J, Borroni E, Wettstein JG, Woltering TJ and Gatti S

    Pharmaceutical Division, Discovery Research CNS and Medicinal Chemistry, F. Hoffmann-La Roche Ltd., 4070 Basel, Switzerland. linda.lundstroem@roche.com

    Binding of the mGlu2/3 antagonist HYDIA in the closed conformation model of mGlu2 causes repulsive interactions with Y216 in lobe II of the binding pocket, preventing closure of the VFT.Modulation of metabotropic glutamate 2/3 receptors represents a promising target for the treatment of neuropsychiatric disorders such as schizophrenia and depression. The novel mGlu2/3 ligand HYDIA ((1S,2R,3R,5R,6S)-2-amino-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid) is a conformationally restricted and hydroxylated glutamate analogue. HYDIA is a potent and selective competitive antagonist of L-glutamate at the mGlu2/3 receptors in spite of being structurally very similar to the bicyclic LY354740, which is a potent and selective mGlu2/3 agonist. By comparing these two ligands, this study delineate the interaction mode of (3)H-HYDIA at the mGlu2 receptor, using both mutagenesis studies and computational modeling. Binding of HYDIA in the closed conformation model of mGlu2 results in repulsive interaction with the Y216 residue, preventing closure of the binding pocket and thus receptor activation. Consequently, HYDIA is proposed to bind in an open conformation model of mGlu2. Mutation of the structurally important Y216 residue in the binding site caused complete loss of affinity of both (3)H-LY354740 and (3)H-HYDIA. T168 in lobe I was shown to have an important role in HYDIA binding, and in the open conformation model this residue is interacting with the amino group of HYDIA. The Y144 residue in lobe I is shown to be engaged in both receptor interlobe binding and ligand interaction. Receptor mutations at this position (Y144G, Y144S and Y144A) showed dramatic impact on binding affinity and functional effect of HYDIA. The mGlu2 receptor mutants with increased structural flexibility at this position, which is crucial for pocket closure, were clearly preferred. These studies highlight the unique properties of the novel (3)H-HYDIA ligand and provide further support to our understanding of binding and signal transduction mechanisms of the mGlu2 receptor.

    ChemMedChem 2009;4;7;1086-94

  • Pharmacogenetics of antipsychotic response in the CATIE trial: a candidate gene analysis.

    Need AC, Keefe RS, Ge D, Grossman I, Dickson S, McEvoy JP and Goldstein DB

    Center for Human Genome Variation, Institute for Genome Sciences & Policy, Duke University, Durham, NC 27708, USA.

    The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Phase 1 Schizophrenia trial compared the effectiveness of one typical and four atypical antipsychotic medications. Although trials such as CATIE present important opportunities for pharmacogenetics research, the very richness of the clinical data presents challenges for statistical interpretation, and in particular the risk that data mining will lead to false-positive discoveries. For this reason, it is both misleading and unhelpful to perpetuate the current practice of reporting association results for these trials one gene at a time, ignoring the fact that multiple gene-by-phenotype tests are being carried out on the same data set. On the other hand, suggestive associations in such trials may lead to new hypotheses that can be tested through both replication efforts and biological experimentation. The appropriate handling of these forms of data therefore requires dissemination of association statistics without undue emphasis on select findings. Here we attempt to illustrate this approach by presenting association statistics for 2769 polymorphisms in 118 candidate genes evaluated for 21 pharmacogenetic phenotypes. On current evidence it is impossible to know which of these associations may be real, although in total they form a valuable resource that is immediately available to the scientific community.

    Funded by: NIMH NIH HHS: N01 MH90001

    European journal of human genetics : EJHG 2009;17;7;946-57

  • The effect of mGluR2 activation on signal transduction pathways and neuronal cell survival.

    Lee HG, Zhu X, Casadesus G, Pallàs M, Camins A, O'Neill MJ, Nakanishi S, Perry G and Smith MA

    Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA. Hyoung-gon.lee@case.edu

    In earlier studies, we found profound alterations in specific signal transduction pathways such as mitogen-activated protein kinase signal pathway that mirrored neuronal cell death in Alzheimer disease (AD). To further delineate the mechanism(s) involved in such aberrant signaling, we subsequently showed that mGluR2 is increased in pyramidal neurons in the hippocampus of AD and often co-localizes with neurofibrillary pathology. Based on these data, we suggested that selective neuronal degeneration in AD may arise through the differential expression and activation of specific receptor populations, such as, mGluR2. In this study, to examine the mechanistic relevance of the above-mentioned in vivo findings, we used cell culture models to show that the activation of mGluR2 leads to the activation of extracellular signal-related kinase (ERK) pathways. Importantly, attesting to the in vivo significance of our findings, this pro-survival signaling pathway is also found to be ectopically activated in AD. We also found that the activation of mGluR2 increases the phosphorylation of tau and that the specific activation of mGluR2 reduces oxidative stress mediated cytotoxicity in neuronal cells. Taken together our findings strongly suggest that mGluR2 may participate in mediating the survival of neurons in the face of selective neuronal dysfunction and degeneration in AD. Additionally, our findings lend support to the notion that tau phosphorylation is a neuroprotective antioxidant response to cellular insults.

    Funded by: NIA NIH HHS: R01 AG024028, R01 AG024028-03

    Brain research 2009;1249;244-50

  • Metabotropic glutamate receptor 2 and 3 gene expression in the human prefrontal cortex and mesencephalon in schizophrenia.

    Ghose S, Crook JM, Bartus CL, Sherman TG, Herman MM, Hyde TM, Kleinman JE and Akil M

    Clinical Brain Disorders Branch, NIMH, NIH, Bethesda, Maryland, USA.

    Group II metabotropic glutamate receptors (mGluR2 and mGluR3) are implicated in schizophrenia. We characterized mGluR2 and 3 mRNA in the human prefrontal cortex (PFC) and mesencephalon, and then compared cases with schizophrenia to matched controls. In the human brain, both receptors were expressed in the PFC and, unlike the rodent, in dopaminergic (DA) cell groups. In schizophrenia, we found significantly higher levels of mGluR2 mRNA in the PFC white matter. The expression of mGluR2, 3 in DA cells provide a mechanism for glutamate to modulate dopamine release in the human brain and this species-specific difference may be critical to understanding rodent models in schizophrenia.

    Funded by: Intramural NIH HHS: Z01 MH002399-18

    The International journal of neuroscience 2008;118;11;1609-27

  • Identification of a serotonin/glutamate receptor complex implicated in psychosis.

    González-Maeso J, Ang RL, Yuen T, Chan P, Weisstaub NV, López-Giménez JF, Zhou M, Okawa Y, Callado LF, Milligan G, Gingrich JA, Filizola M, Meana JJ and Sealfon SC

    Department of Neurology, Mount Sinai School of Medicine, New York, New York 10029, USA. javier.maeso@mssm.edu

    The psychosis associated with schizophrenia is characterized by alterations in sensory processing and perception. Some antipsychotic drugs were identified by their high affinity for serotonin 5-HT2A receptors (2AR). Drugs that interact with metabotropic glutamate receptors (mGluR) also have potential for the treatment of schizophrenia. The effects of hallucinogenic drugs, such as psilocybin and lysergic acid diethylamide, require the 2AR and resemble some of the core symptoms of schizophrenia. Here we show that the mGluR2 interacts through specific transmembrane helix domains with the 2AR, a member of an unrelated G-protein-coupled receptor family, to form functional complexes in brain cortex. The 2AR-mGluR2 complex triggers unique cellular responses when targeted by hallucinogenic drugs, and activation of mGluR2 abolishes hallucinogen-specific signalling and behavioural responses. In post-mortem human brain from untreated schizophrenic subjects, the 2AR is upregulated and the mGluR2 is downregulated, a pattern that could predispose to psychosis. These regulatory changes indicate that the 2AR-mGluR2 complex may be involved in the altered cortical processes of schizophrenia, and this complex is therefore a promising new target for the treatment of psychosis.

    Funded by: Medical Research Council: MRC_G9811527; NIDA NIH HHS: P01 DA012923, P01 DA012923-06A10004, T32 DA007135, T32 DA007135-25S1; NIGMS NIH HHS: T32 GM062754; NIMH NIH HHS: U01 MH083545

    Nature 2008;452;7183;93-7

  • The metabotropic glutamate 2/3 receptor agonist LY404039 reduces alcohol-seeking but not alcohol self-administration in alcohol-preferring (P) rats.

    Rodd ZA, McKinzie DL, Bell RL, McQueen VK, Murphy JM, Schoepp DD and McBride WJ

    Department of Psychiatry, Indiana University School of Medicine, Institute of Psychiatric Research, Indianapolis, 46202-4887, USA. zrodd@iupui.edu

    Metabotropic glutamate (mGlu) receptors have been shown to mediate a number of behaviors including emotionality and responsivity to stress as demonstrated by efficacy in preclinical and clinical studies. The objective of this study was to assess the effects of the mGlu2/3 receptor agonist LY404039 (LY) on operant ethanol (EtOH) self-administration during alcohol seeking (pavlovian spontaneous recovery, PSR), alcohol relapse (alcohol deprivation effect, ADE), and maintenance responding for alcohol. Adult alcohol-preferring (P) rats were trained in 2-lever operant chambers to self-administer 15% EtOH (v/v) and water on a concurrent fixed-ratio 5-fixed-ratio 1 (FR5-FR1) schedule of reinforcement in daily 1h sessions. After at least 10 weeks of daily 1 h sessions, rats underwent seven extinction sessions, followed by 2 weeks of no manipulation, and then rats were tested for the expression of an EtOH PSR for four sessions. Rats were then given a week in their home cage before being returned to the operant chambers with access to EtOH and water (alcohol relapse). Finally, the effects of LY upon maintenance EtOH and water responding were assessed once stable responding was reestablished. The mGlu2/3 receptor agonist LY404039 reduced responding on the EtOH in the PSR test. LY also reduced the expression of an alcohol deprivation effect (ADE) during relapse, but did not reduce EtOH responding under maintenance conditions. The results of this study demonstrate that activating mGlu2/3 receptors inhibits the expression of alcohol seeking and relapse behavior without altering alcohol self-administration behavior.

    Funded by: NIAAA NIH HHS: AA07611, AA10721

    Behavioural brain research 2006;171;2;207-15

  • Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes.

    Kimura K, Wakamatsu A, Suzuki Y, Ota T, Nishikawa T, Yamashita R, Yamamoto J, Sekine M, Tsuritani K, Wakaguri H, Ishii S, Sugiyama T, Saito K, Isono Y, Irie R, Kushida N, Yoneyama T, Otsuka R, Kanda K, Yokoi T, Kondo H, Wagatsuma M, Murakawa K, Ishida S, Ishibashi T, Takahashi-Fujii A, Tanase T, Nagai K, Kikuchi H, Nakai K, Isogai T and Sugano S

    Life Science Research Laboratory, Central Research Laboratory, Hitachi, Ltd., Kokubunji, Tokyo, 185-8601, Japan.

    By analyzing 1,780,295 5'-end sequences of human full-length cDNAs derived from 164 kinds of oligo-cap cDNA libraries, we identified 269,774 independent positions of transcriptional start sites (TSSs) for 14,628 human RefSeq genes. These TSSs were clustered into 30,964 clusters that were separated from each other by more than 500 bp and thus are very likely to constitute mutually distinct alternative promoters. To our surprise, at least 7674 (52%) human RefSeq genes were subject to regulation by putative alternative promoters (PAPs). On average, there were 3.1 PAPs per gene, with the composition of one CpG-island-containing promoter per 2.6 CpG-less promoters. In 17% of the PAP-containing loci, tissue-specific use of the PAPs was observed. The richest tissue sources of the tissue-specific PAPs were testis and brain. It was also intriguing that the PAP-containing promoters were enriched in the genes encoding signal transduction-related proteins and were rarer in the genes encoding extracellular proteins, possibly reflecting the varied functional requirement for and the restricted expression of those categories of genes, respectively. The patterns of the first exons were highly diverse as well. On average, there were 7.7 different splicing types of first exons per locus partly produced by the PAPs, suggesting that a wide variety of transcripts can be achieved by this mechanism. Our findings suggest that use of alternate promoters and consequent alternative use of first exons should play a pivotal role in generating the complexity required for the highly elaborated molecular systems in humans.

    Genome research 2006;16;1;55-65

  • 3-(2-Ethoxy-4-{4-[3-hydroxy-2-methyl-4-(3-methylbutanoyl)phenoxy]butoxy}phenyl)propanoic acid: a brain penetrant allosteric potentiator at the metabotropic glutamate receptor 2 (mGluR2).

    Cube RV, Vernier JM, Hutchinson JH, Gardner MF, James JK, Rowe BA, Schaffhauser H, Daggett L and Pinkerton AB

    Department of Chemistry, Merck Research Laboratories, MRLSDB2, 3535 General Atomics Court, San Diego, CA 92121, USA. rowena_cube@merck.com

    We have identified and synthesized a brain penetrant propanoic acid as an allosteric potentiator of the metabotropic glutamate receptor 2. Structure-activity relationship studies directed toward improving the potency, level of potentiation and brain penetration led to the discovery of 8 (EC50=1200 nM, 77% potentiation, 119% brain/plasma in rat, 20 mpk i.p., brain level of 5700 nM).

    Bioorganic & medicinal chemistry letters 2005;15;9;2389-93

  • The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

    Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Morrin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J and MGC Project Team

    The National Institutes of Health's Mammalian Gene Collection (MGC) project was designed to generate and sequence a publicly accessible cDNA resource containing a complete open reading frame (ORF) for every human and mouse gene. The project initially used a random strategy to select clones from a large number of cDNA libraries from diverse tissues. Candidate clones were chosen based on 5'-EST sequences, and then fully sequenced to high accuracy and analyzed by algorithms developed for this project. Currently, more than 11,000 human and 10,000 mouse genes are represented in MGC by at least one clone with a full ORF. The random selection approach is now reaching a saturation point, and a transition to protocols targeted at the missing transcripts is now required to complete the mouse and human collections. Comparison of the sequence of the MGC clones to reference genome sequences reveals that most cDNA clones are of very high sequence quality, although it is likely that some cDNAs may carry missense variants as a consequence of experimental artifact, such as PCR, cloning, or reverse transcriptase errors. Recently, a rat cDNA component was added to the project, and ongoing frog (Xenopus) and zebrafish (Danio) cDNA projects were expanded to take advantage of the high-throughput MGC pipeline.

    Funded by: PHS HHS: N01-C0-12400

    Genome research 2004;14;10B;2121-7

  • Glial proliferation and metabotropic glutamate receptor expression in amyotrophic lateral sclerosis.

    Anneser JM, Chahli C, Ince PG, Borasio GD and Shaw PJ

    Department of Neurology, Ludwig-Maximilians-University, Klinikum Grosshadern, Munich, Germany. Johanna.Anneser@nro.med.uni-muenchen.de

    Accumulating evidence indicates that alterations in glial activation and disturbances in glial glutamate metabolism may contribute to the pathogenesis of amyotrophic lateral sclerosis (ALS). Metabotropic glutamate receptors (mGluRs) are involved in glutamate homeostasis as well as in glial proliferation. Using in situ hybridization and immunohistochemistry we found a strong upregulation of group I and group II mGluR mRNA and protein in ALS spinal cord as compared to controls (mGluR5 > mGluR1 > mGluR2/3). In vitro, the mGluR group I agonist 3,5-dihydroxyphenylglycine induced proliferation in chick spinal cord astroglial cultures. Moreover, addition of cerebrospinal fluid (CSF) from ALS patients resulted in significantly higher proliferation rates than control CSF. In both cases, the effect could be blocked by addition of the mGluR group I antagonist 1-aminoindan-1,5-dicarboxylic acid. Taken together, our data suggest that stimulation of glial mGluRs through mediators present in the CSF may contribute to glial proliferation and astrogliosis in ALS.

    Journal of neuropathology and experimental neurology 2004;63;8;831-40

  • Metabotropic glutamate receptor 2/3 in the hippocampus of patients with mesial temporal lobe epilepsy, and of rats and mice after pilocarpine-induced status epilepticus.

    Tang FR, Chia SC, Chen PM, Gao H, Lee WL, Yeo TS, Burgunder JM, Probst A, Sim MK and Ling EA

    Epilepsy Research Laboratories, National Neuroscience Institute, Singapore. Feng_Ru_Tang@ttsh.com.sg

    A comparative study of the expression of metabotropic glutamate receptor 2/3 (mGluR2/3) was done in the hippocampus of rats and mice after pilocarpine-induced status epilepticus (APISE), and of patients with mesial temporal lobe epilepsy. At 1 day APISE, there was a marked increase in mGluR2/3 immunoreactivity in the stratum lacunosum moleculare (SLM) of CA1 area and in the middle one-third of the molecular layer (MM) of the dentate gyrus. Immuno-electron microscopic study showed degenerating mGluR2/3 positive axons in the SLM of CA1 area at 1 day APISE. From 7 days, mGluR2/3 immunopositive product decreased, and by 31 days APISE, it almost disappeared in two-thirds of the SLM near CA2. In the mouse model at 2 months APISE, mGluR2/3 immunopositive product in two-thirds of the SLM near the stratum radiatum disappeared, and so did in the whole SLM of CA1 area in patients with mesial temporal lobe epilepsy. Neuropharmacological study by intravenous injection of mGluR2/3 agonist 2R,4R-4-aminopyrrolidine-2,4-dicarboxylate [(2R,4R)-APDC] at different doses at 1h during pilocarpine induced status epilepticus showed that (2R,4R)-APDC could not stop seizures and neuronal death in the hilus of the dentate gyrus. The present study, therefore, suggests that the reduction of mGluR2/3 immunopositive product in the SLM of CA1 is a consequence of neuronal loss in either the entorhinal cortex or CA1 area of the hippocampus, and at the dosage range from 12.5 to 600 mg/kg, (2R,4R)-APDC may not be effective in the prevention of seizures or neuronal death in the hilus of the dentate gyrus.

    Epilepsy research 2004;59;2-3;167-80

  • A small modulatory dsRNA specifies the fate of adult neural stem cells.

    Kuwabara T, Hsieh J, Nakashima K, Taira K and Gage FH

    Laboratory of Genetics, The Salk Institute, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.

    Discovering the molecular mechanisms that regulate neuron-specific gene expression remains a central challenge for CNS research. Here, we report that small, noncoding double-stranded (ds) RNAs play a critical role in mediating neuronal differentiation. The sequence defined by this dsRNA is NRSE/RE1, which is recognized by NRSF/REST, known primarily as a negative transcriptional regulator that restricts neuronal gene expression to neurons. The NRSE dsRNA can trigger gene expression of neuron-specific genes through interaction with NRSF/REST transcriptional machinery, resulting in the transition from neural stem cells with neuron-specific genes silenced by NRSF/REST into cells with neuronal identity that can express neuronal genes. The mechanism of action appears to be mediated through a dsRNA/protein interaction, rather than through siRNA or miRNA. The discovery of small modulatory dsRNAs (smRNAs) extends the important contribution of noncoding RNAs as key regulators of cell behavior at both transcriptional and posttranscriptional levels.

    Cell 2004;116;6;779-93

  • Presynaptic group II metabotropic glutamate receptors reduce stimulated and spontaneous transmitter release in human dentate gyrus.

    Dietrich D, Kral T, Clusmann H, Friedl M and Schramm J

    Experimental Neurophysiology, Department of Neurosurgery, University Clinic Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany. dirk.dietrich@ukb.uni-bonn.de

    Metabotropic glutamate receptors (mGluRs) control excitatory neurotransmission as inhibitory autoreceptors at many synapses throughout the CNS. Since pharmacological activation of mGluRs potently depresses excitatory transmission, anticonvulsive effects were found in a number of experimental epilepsies. However, although native rodent mGluRs and heterologously expressed human mGluRs have so far been investigated in great detail, our knowledge about native human mGluRs in situ is limited. Here we used acute human hippocampal slices prepared from hippocampi surgically removed for the treatment of temporal lobe epilepsy in order to investigate the modulation of glutamatergic transmission by human mGluRs at the perforant path-granule cell synapse. The broad spectrum mGluR agonist (1S, 3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD) profoundly and reversibly reduced field EPSPs (fEPSPs) with an EC(50) of 30+/-7.4 microM. Paired-pulse depression of fEPSPs was converted into strong facilitation. The inhibition of fEPSPs by ACPD was mimicked by the specific group II mGluR agonist (2S, 2'R, 3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (DCG-IV), while the specific group I agonist (S)-3,5-dihydroxyphenylglycine (DHPG) was ineffective. The effect of ACPD was blocked by group II antagonist (2S,3S,4S)-2methyl-2-(carboxycyclopropyl)glycine (MCCG) but was not changed by coapplication of the specific group III antagonist (S)2 amino2methyl4phosphonobutanoic acid (MAP4). ACPD reduced pharmacologically isolated intracellular EPSPs in granule cells to the same extent as fEPSPs, whereas a specific group III agonist had no effect on EPSPs. Whole-cell recordings from morphologically identified granule cells revealed that DCG-IV significantly reduced the frequency of miniature EPSCs (mEPSCs) in granule cells while the mean amplitude of mEPSCs was not affected. We conclude that in human dentate gyrus mGluR2/3 can almost completely depress glutamate release by a presynaptic mechanism which acts downstream of presynaptic voltage gated calcium-entry and most likely involves a direct modulation of the release machinery.

    Neuropharmacology 2002;42;3;297-305

  • Tamalin, a PDZ domain-containing protein, links a protein complex formation of group 1 metabotropic glutamate receptors and the guanine nucleotide exchange factor cytohesins.

    Kitano J, Kimura K, Yamazaki Y, Soda T, Shigemoto R, Nakajima Y and Nakanishi S

    Department of Biological Sciences, Faculty of Medicine, Graduate School of Biostudies, Kyoto University, Kyoto, 606-8501, Japan.

    In this investigation, we report identification and characterization of a 95 kDa postsynaptic density protein (PSD-95)/discs-large/ZO-1 (PDZ) domain-containing protein termed tamalin, also recently named GRP1-associated scaffold protein (GRASP), that interacts with group 1 metabotropic glutamate receptors (mGluRs). The yeast two-hybrid system and in vitro pull-down assays indicated that the PDZ domain-containing, amino-terminal half of tamalin directly binds to the class I PDZ-binding motif of group 1 mGluRs. The C-terminal half of tamalin also bound to cytohesins, the members of guanine nucleotide exchange factors (GEFs) specific for the ADP-ribosylation factor (ARF) family of small GTP-binding proteins. Tamalin mRNA is expressed predominantly in the telencephalic region and highly overlaps with the expression of group 1 mGluR mRNAs. Both tamalin and cytohesin-2 were enriched and codistributed with mGluR1a in postsynaptic membrane fractions. Importantly, recombinant and native mGluR1a/tamalin/cytohesin-2 complexes were coimmunoprecipitated from transfected COS-7 cells and rat brain tissue, respectively. Transfection of tamalin and mutant tamalin lacking a cytohesin-binding domain caused an increase and decrease in cell-surface expression of mGluR1a in COS-7 cells, respectively. Furthermore, adenovirus-mediated expression of tamalin and dominant-negative tamalin facilitated and reduced the neuritic distribution of endogenous mGluR5 in cultured hippocampal neurons, respectively. The results indicate that tamalin plays a key role in the association of group 1 mGluRs with the ARF-specific GEF proteins and contributes to intracellular trafficking and the macromolecular organization of group 1 mGluRs at synapses.

    The Journal of neuroscience : the official journal of the Society for Neuroscience 2002;22;4;1280-9

  • Human metabotropic glutamate receptor 2 gene (GRM2): chromosomal sublocalization (3p21.1-p21.2) and genomic organization.

    Martí SB, Cichon S, Propping P and Nöthen M

    Institute of Human Genetics, University of Bonn, Bonn, Germany. borts@tcd.ie

    Imbalances in glutamatergic function have been implicated in the pathogenesis of neuropsychiatric disorders. Consequently, glutamate receptors genes are promising candidates in search of susceptibility genes for these disorders. In the present study, we report the chromosomal sublocalization and genomic organization of the human metabotropic glutamate receptor 2 gene (GRM2). Using monochromosomal hybrid cell lines of NIGMS Mapping Panel 2 (Coriell Cell Repository), the GRM2 gene was localized to human chromosome 3, confirming previously reported localization. In addition, using the radiation hybrid panel RH3 (Research Genetics), we sublocalized the GRM2 gene to chromosomal region 3p21.1-p21.2. The genomic organization of the GRM2 gene was established using a premade library of adaptor-ligated, human-specific genomic DNA fragments. The gene consists of 5 exons, with sizes ranging from 74 to 1,076 bp.

    American journal of medical genetics 2002;114;1;12-4

  • Control of kinetic properties of GluR2 flop AMPA-type channels: impact of R/G nuclear editing.

    Krampfl K, Schlesinger F, Zörner A, Kappler M, Dengler R and Bufler J

    Department of Neurology, Medizinische Hochschule Hannover, 31623 Hannover, Germany.

    The GluR2 flop subunit of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-type glutamate receptors greatly determines calcium permeability and kinetic properties of heteromeric AMPA subunit assemblies. Post-transcriptional editing of this subunit at the Q/R/N site controls calcium permeability whereas editing at the R/G site is involved in the regulation of biophysical properties. We used patch-clamp techniques with ultrafast solution exchange to examine the kinetics of recombinant human homomeric GluR2 flop channels transiently expressed in HEK293 cells [edited at the R/G site and Q/R/N site (GR), and unedited (RN) and edited (GN) at the R/G site both with asparagine (N) at the Q/R/N site]. The time constant of desensitization after application of 10 mm glutamate was 1.38 +/- 0.05 ms (n = 10), 5.53 +/- 0.57 ms (n = 7) and 1.33 +/- 0.06 ms (n = 12) for the GluR2 flop GR, RN and GN channels, respectively. The time constant of resensitization was 75 ms for the GluR2 flop RN and 30 ms for the GN channels. The dose-dependence of the peak current amplitude, kinetics of activation and deactivation, and peak open probability did not differ between RN and GN channels. The study shows that desensitization and resensitization kinetics of homomeric GluR2 flop channels are controlled by a single amino acid exchange (glycine by arginine) at the R/G site. Quantitative analysis by computer simulation using a circular kinetic scheme allows the prediction of the main experimental results.

    The European journal of neuroscience 2002;15;1;51-62

  • Identification of essential residues involved in the glutamate binding pocket of the group II metabotropic glutamate receptor.

    Malherbe P, Knoflach F, Broger C, Ohresser S, Kratzeisen C, Adam G, Stadler H, Kemp JA and Mutel V

    Pharma Division, Preclinical Research, Nervous System Diseases, F. Hoffmann-La Roche Ltd., Basel, Switzerland.

    Metabotropic glutamate (mGlu) receptors are a family of G-protein-coupled receptors that play central roles as modulators of both glutamatergic and other major neurotransmitter systems in CNS. Using molecular modeling, site-directed mutagenesis, [(3)H]LY354740 binding, [(35)S]GTPgammaS binding, and activation of GIRK current, we have been able to identify residues crucial for the binding of LY354740 and glutamate to rat mGlu2 receptors. Several of the crucial residues located in the binding site (Arg-57, Tyr-144, Tyr-216, Asp-295) have not been identified previously. We propose that the gamma-carboxyl group of LY354740 forms H-bonds to Arg-57, whereas the alpha-carboxyl group forms an H-bond with the hydroxyl group of Ser-145. The alpha-amino group of LY354740 forms H-bonds to Asp-295 and to the side-chain hydroxyl group of Thr-168. In addition, Tyr-144 may establish a hydrophobic (C-H/pi)-interaction with the bicyclo-hexane ring of LY354740. Furthermore, the mutation of residues Ser-148 and Arg-183, which are too remote for a direct interaction, affected the ligand affinity dramatically. These results suggest that Ser-148 and Arg-183 may be important for the 3D structure and/or are involved in closure of the domain. Finally, Asp-146, which is also remote from the binding site, was shown to be involved in the differential binding affinity of [(3)H]LY354740 for mGlu2 versus mGlu3 receptors. All the mGlu receptors except mGlu2 are activated by Ca(2+) and have serine instead of aspartic acid at this position, which suggests a critical role of this aspartic acid residue in the binding properties of this unique receptor.

    Molecular pharmacology 2001;60;5;944-54

  • Structure and polymorphisms of the human metabotropic glutamate receptor type 2 gene (GRM2): analysis of association with schizophrenia.

    Joo A, Shibata H, Ninomiya H, Kawasaki H, Tashiro N and Fukumaki Y

    Division of Disease Genes, Institute of Genetic Information, Kyushu University, Fukuoka, Japan.

    Metabotropic glutamate receptors (mGluRs) belong to the class of GTP-binding protein coupled receptors and consist of eight different subtypes. The subtype 2 metabotropic glutamate receptor (mGluR2) gene (GRM2) is one of the possible candidate genes for schizophrenia. Phencyclidine (PCP)-induced increase in glutamate efflux and schizophrenia-like behavioral abnormalities were reduced by pretreatment of the mGluRII agonist LY354740 in rats and its effects are mediated via mGluR2. To evaluate involvement of the mGluR2 gene in the pathogenesis of schizophrenia, we isolated the human mGluR2 gene and determined the transcription initiation site, the entire nucleotide sequence and the chromosomal localization. The hmGluR2 gene spans 13 kb with six exons, including one non-coding exon. The gene was mapped to chromosome 3 p12-p11 by Radiation Hybrid Panel analysis. We screened polymorphisms in the coding exons of the mGluR2 gene, using the SSCP procedure. The thirteen polymorphisms identified included ten missense, one silent mutation and two one-base substitutions in the 5'-untranslated region. We genotyped 213 Japanese schizophrenics and 220 controls to study the association of polymorphisms in the mGluR2 gene with schizophrenia. As we found no statistically significant differences in allele frequencies of each polymorphism, these polymorphisms apparently do not play a major role in schizophrenia.

    Molecular psychiatry 2001;6;2;186-92

  • GTPase activating specificity of RGS12 and binding specificity of an alternatively spliced PDZ (PSD-95/Dlg/ZO-1) domain.

    Snow BE, Hall RA, Krumins AM, Brothers GM, Bouchard D, Brothers CA, Chung S, Mangion J, Gilman AG, Lefkowitz RJ and Siderovski DP

    Amgen Institute, Toronto, Ontario M5G 2C1, Canada.

    Regulator of G-protein signaling (RGS) proteins increase the intrinsic guanosine triphosphatase (GTPase) activity of G-protein alpha subunits in vitro, but how specific G-protein-coupled receptor systems are targeted for down-regulation by RGS proteins remains uncharacterized. Here, we describe the GTPase specificity of RGS12 and identify four alternatively spliced forms of human RGS12 mRNA. Two RGS12 isoforms of 6.3 and 5.7 kilobases (kb), encoding both an N-terminal PDZ (PSD-95/Dlg/ZO-1) domain and the RGS domain, are expressed in most tissues, with highest levels observed in testis, ovary, spleen, cerebellum, and caudate nucleus. The 5.7-kb isoform has an alternative 3' end encoding a putative C-terminal PDZ domain docking site. Two smaller isoforms, of 3.1 and 3.7 kb, which lack the PDZ domain and encode the RGS domain with and without the alternative 3' end, respectively, are most abundantly expressed in brain, kidney, thymus, and prostate. In vitro biochemical assays indicate that RGS12 is a GTPase-activating protein for Gi class alpha subunits. Biochemical and interaction trap experiments suggest that the RGS12 N terminus acts as a classical PDZ domain, binding selectively to C-terminal (A/S)-T-X-(L/V) motifs as found within both the interleukin-8 receptor B (CXCR2) and the alternative 3' exon form of RGS12. The presence of an alternatively spliced PDZ domain within RGS12 suggests a mechanism by which RGS proteins may target specific G-protein-coupled receptor systems for desensitization.

    Funded by: NHLBI NIH HHS: HL16037; NIGMS NIH HHS: GM34497

    The Journal of biological chemistry 1998;273;28;17749-55

  • Coupling of metabotropic glutamate receptors 2 and 4 to G alpha 15, G alpha 16, and chimeric G alpha q/i proteins: characterization of new antagonists.

    Gomeza J, Mary S, Brabet I, Parmentier ML, Restituito S, Bockaert J and Pin JP

    UPR Centre Nationale de Recherche Scientifique 9023, Mécanismes Moléculaires des Communications Cellulaires, CCIPE, Montpeller, France.

    Together with the calcium-sensing receptor, the metabotropic glutamate receptors (mGluRs) share no sequence homology with the other G protein-coupled receptors (GPCRs) and therefore constitute a new family of receptors. Recently, it was reported that G alpha 15 and G alpha 16 subunits allow many GPCRs to activate phospholipase C (PLC). Furthermore, the exchange of a few carboxyl-terminal residues of G alpha q by those of G alpha 12 or G alpha o allows the resulting chimeric G alpha subunits (G alpha ql and G alpha qol respectively) to couple Gi-coupled receptors to PLC. We report that mGluR2 and mGluR4, two receptors negatively coupled to adenylyl cyclase, activate PLC when coexpressed with G alpha 15, G alpha ql or G alpha qo. This indicates that the carboxyl-terminal end of the G alpha subunit also plays an important role in the specific interaction between mGluRs and the G proteins. In addition, the measurement of PLC activation by Gi-coupled mGluRs coexpressed with these G alpha subunits constitutes an easy functional assay for the pharmacological characterization of these receptors. The rank order of potency of antagonists was found to be (2S,3S,4S)-2-methyl-2-(carboxycyclopropyl)glycine approximately (R,S)- alpha-methyl-4-phosphonophenylglycine > (R,S)-alpha-methyl-4-sulfonophenylglycine > (R,S)-alpha-methyl-4-tetrazolylphenylglycine = (S)-2-amino-2-methyl-4-phosphonobutyrate for mGluR2 and to be (R,S)-alpha-methyl-4-phosphonophenylglycine > or = (S)-2-amino-2-methyl-4-phosphonobutyrate > > (R,S)-alpha-methyl-4-sulfonophenylglycine [(R,S)-alpha-methyl-4-tetrazolylphenylglycine and (2S,3S,4S)-2-methyl-2-(carboxycyclopropyl)glycine being inactive at 1 mM] for mGluR4. Using this functional assay, (R,S)-alpha-methyl-4-phosphonophenylglycine was found to have a similar KB value for mGluR2 and mGluR4.

    Molecular pharmacology 1996;50;4;923-30

  • Localization of two metabotropic glutamate receptor genes, GRM3 and GRM8, to human chromosome 7q.

    Scherer SW, Duvoisin RM, Kuhn R, Heng HH, Belloni E and Tsui LC

    Department of Molecular and Medical Genetics, University of Toronto, Ontario, Canada.

    Metabotropic glutamate receptors (GRMs) are neurotransmitter receptors that respond to glutamate stimulations by activating GTP-binding proteins and modulating second-messenger cascades. Eight related GRMs have been identified to date. In this study, we have mapped GRM3 and GRM8 to human chromosome 7q21.1-q21.2 and 7q31.3-q32.1, respectively, using somatic cell hybrid and fluorescence in situ hybridization analysis. A yeast artificial chromosome contig was constructed surrounding the genes, allowing their location to be integrated into the genetic and physical map of chromosome 7.

    Funded by: NEI NIH HHS: EY09534

    Genomics 1996;31;2;230-3

  • Molecular cloning, functional expression and pharmacological characterization of the human metabotropic glutamate receptor type 2.

    Flor PJ, Lindauer K, Püttner I, Rüegg D, Lukic S, Knöpfel T and Kuhn R

    Department of Molecular and Cellular Biology, CNS Research, Ciba, Basle, Switzerland.

    A cDNA encoding the human metabotropic glutamate receptor type 2 (hmGluR2) was isolated from human brain cDNA libraries by cross-hybridization with rat mGluR2 probes. The deduced amino acid sequence of the human mGluR2 receptor consists of 872 residues and shows a sequence identity of 97% to the amino acid sequence of rat mGluR2. Northern blot analyses showed that hmGluR2 is widely expressed in different regions of the adult brain as well as in fetal human brain. Genomic Southern blotting localized the mGluR2 gene to human chromosome 3. Chinese hamster ovary (CHO) cells stably transfected with the cloned hmGluR2 cDNA exhibit agonist induced depression of forskolin-stimulated cAMP accumulation. A direct comparison of CHO cells stably expressing human and rat mGluR2 with five agonists revealed the same rank order of potency [(2S,3S,4S)-alpha-(carboxycyclopropyl)-glycine > (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid = L-glutamate > quisqualate = L-2-amino-4-phosphonobutyric acid] and similar EC50 values for both homologous receptors. (R,S)-alpha-methyl-4-carboxyphenylglycine, a reported antagonist at some mGluR subtypes, reduced the depression of forskolin-induced cAMP accumulation by (1S,3R)-ACPD in both human and rat mGluR2.

    The European journal of neuroscience 1995;7;4;622-9

Gene lists (3)

Gene List Source Species Name Description Gene count
L00000061 G2C Homo sapiens BAYES-COLLINS-MOUSE-PSD-CONSENSUS Mouse cortex PSD consensus (ortho) 984
L00000069 G2C Homo sapiens BAYES-COLLINS-HUMAN-PSD-FULL Human cortex biopsy PSD full list 1461
L00000071 G2C Homo sapiens BAYES-COLLINS-MOUSE-PSD-FULL Mouse cortex PSD full list (ortho) 1556
© G2C 2014. The Genes to Cognition Programme received funding from The Wellcome Trust and the EU FP7 Framework Programmes:
EUROSPIN (FP7-HEALTH-241498), SynSys (FP7-HEALTH-242167) and GENCODYS (FP7-HEALTH-241995).

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