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Determination of the Genomic Structure and Mutation Screening In Molecular Psychiatry (2002) 7, 508–514 2002 Nature Publishing Group All rights reserved 1359-4184/02 $25.00 www.nature.com/mp ORIGINAL RESEARCH ARTICLE Determination of the genomic structure and mutation screening in schizophrenic individuals for five subunits of the N-methyl-D-aspartate glutamate receptor NM Williams*, T Bowen*, G Spurlock, N Norton, HJ Williams, B Hoogendoorn, MJ Owen and MC O’Donovan Department of Psychological Medicine, University of Wales College of Medicine, Heath Park, Cardiff, CF14 4XN, UK The glutamatergic system is the major excitatory neurotransmitter system in the CNS. Gluta- mate receptors, and in particular N-methyl-D-aspartate (NMDA) receptors, have been proposed as mediators of many common neuropsychiatric phenotypes including cognition, psychosis, and degeneration. We have reconstructed the genomic structure of all five genes encoding NMDA receptors in silico. We screened each for sequence variation and estimated the allele frequencies of all detected SNPs in pooled samples of 184 UK Caucasian schizophrenics and 184 UK Caucasian blood donor controls. Only a single non-synonymous polymorphism was found indicating extreme selection pressure. The rarity of non-synonymous changes suggests that such variants are unlikely to make a common contribution to common phenotypes. We found a further 26 polymorphisms within exonic or adjacent intronic sequences. The minor alleles of most of these have a relatively high frequency (63% above 0.2). These SNPs will therefore be suitable for studying neuropsychiatric phenotypes that are putatively related to NMDA dysfunction. Pooled analysis provided no support for association between any of the GRIN genes and schizophrenia. Molecular Psychiatry (2002) 7, 508–514. doi:10.1038/sj.mp.4001030 Keywords: candidate gene; NMDA; polymorphism; glutamate Introduction transmission, these include neuronal migration, pro- liferation and excitability, synapse formation, stability The glutamatergic system is the major excitatory neuro- and plasticity, and long term potentiation.4–6 Because transmitter system in the CNS. Glutamatergic trans- of these wide-ranging functions, altered glutamatergic mission is mediated by receptor families that are neurotransmission has been implicated in many differ- classed ionotropic (iGluRs) and metabotropic ent CNS processes, physiological and pathological. (mGluRs). iGluRs are ligand-gated ion channels, which These include learning and learning disability, mem- can in turn be sub-classified into the following groups ory, epilepsy, CNS recovery after trauma or ischaemia, based upon their ligand binding properties: N-methyl neurodegenerative diseases, schizophrenia, affective D-aspartate receptors (NMDA), alpha-amino-3-hyd- disorder, and alcohol dependence.6–9 While more than roxy-5-methyl-4-isoxazole propionate receptors 30 glutamatergic related cDNAs have been cloned in (AMPA), kainate (KA) and more recently delta. The humans, the genomic structure of most has not been majority of iGluRs are thought to be tetrameric or pen- determined experimentally. This has obviously been tameric heteromultimers although the stoichiometry an obstacle to molecular genetic tests of the glutamate and precise composition of native receptors is at hypotheses of the neuropsychiatric disorders men- present unknown.1 In addition to a multiplicity of tioned above. genes, the diversity of iGluRs is increased by the poten- All glutamatergic related genes are good candidates tial for numerous sub-unit combinations of heteromul- for several neuropsychiatric disorders, but region- timers, by alternative splicing, and by RNA editing.1–3 selective knock out studies in animals suggest that Given their diversity, it is not surprising that gluta- NMDA sub-units have probably the strongest a priori matergic neurotransmission has a role in many basic case for several phenotypes including learning and neuronal functions. In addition to fast synaptic memory.7,8 Moreover, reduced expression of GRIN1 leads to behavioural abnormalities in mice that are similar to those observed in pharmacologically Correspondence: M O’Donovan, Department of Psychological induced models of schizophrenia.9 We have therefore Medicine, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN, UK. E-mail: odonovanmcȰcardiff.ac.uk targeted NMDA receptors as a priority for molecular *These authors contributed equally to the paper. genetic analysis. Five genes encoding NMDA sub-units Received 27 September 2001; accepted 12 November 2001 have been identified in humans. NMDAR1 sub-units Polymorphisms in NMDA subunit genes NM Williams et al 509 are encoded by GRIN1 and are believed to be common Because we were concerned that reagents in the GC- to all native NMDA receptors.10 NMDA receptors are Rich kit might alter the melting characteristics of DNA, also thought to contain one or more NMDAR2 sub- the optimal DHPLC conditions for fragments amplified units from the family of NMDAR2A-D proteins, which using this method were determined empirically as are encoded by GRIN2A-D respectively. To facilitate described elsewhere.16 Where DHPLC analysis sug- candidate gene studies of NMDA receptors, we have gested that a subject was heterozygous, the PCR pro- reconstructed in silico the genomic structure of the 4 ducts from that individual were sequenced to deter- GRIN2 genes to complement the known structure of mine the nature of the polymorphism using the Big Dye GRIN1, and subjected all the genes to mutation analysis Terminator Cycle Sequencing Kit (Perkin Elmer using denaturing high performance liquid chromato- Applied Biosystems, Cheshire, UK) as described by the graphy (DHPLC) and sequencing. manufacturer. All variants were confirmed by allele specific primer extension using SNaPshot chemistry (Perkin Elmer Applied Biosystems) using PCR pro- Materials and methods ducts from a homozygote and a putative heterozygote Genomic structure and PCR as template. The allele frequency of each polymor- The genomic sequence of GRIN1 was previously phism was estimated in 184 UK Caucasian blood reported11 and is available (Acc No: Z32772; Z32773; donors and 184 UK Caucasian schizophrenics by an Z32774). However, the annotation is inaccurate and the accurate method of pooled genotyping based upon sequences specified as exons do not include either 5Ј HPLC analysis of primer extension products17 or by or 3Ј UTRs. The genomic structure for GRIN1 including SNaPshot assay. The latter method has in our hands both the 5Ј and 3Ј UTRs was determined as described proved equally as accurate as the HPLC method below. For GRIN2A-D we identified genomic clones by (manuscript in preparation). aligning each of their respective reference cDNA sequences with the genomic sequence data deposited Subjects in the ‘non-redundant’ and ‘high-throughput sequen- All subjects used in this study were unrelated Caucasi- cing’ GenBank databases using BasicBLAST search12 ans born in the UK or Ireland. All cases met the DSM- (http://www.ncbi.nlm.nih.gov/blast/blast.cgi). BLAST2 IV18 criteria for schizophrenia with diagnosis being sequences13 (http://www.ncbi.nlm.nih.gov/blast/bl2seq/ determined using OPCRIT version 3.3119 following a bl2.html) was then used to perform a gapped alignment semi-structured interview, SCAN or PSE,20,21 and between each cDNA and its corresponding genomic examination of case notes. The sample for mutation clone in order to determine its intron/exon structure. screening consisted of 14 unrelated cases who also had Genomic clones were only selected if they mapped to at least one first degree relative who suffered from the same region as the gene and if each exon had at schizophrenia and were selected randomly from famil- least 95% homology with the reference cDNA ies ascertained for linkage analysis. Allele frequencies sequence. The derived genomic sequences were used were estimated in DNA pools constructed from 184 to design primers using Primer3 (http://www-genome. controls and 184 cases meeting DSM-IV criteria for wi.mit.edu/cgi-bin/primer/primer3Fwww.cgi). In order schizophrenia. Local Research Ethics Committee not to compromise the sensitivity of mutation approval was obtained, and subjects gave written infor- screening, large exons were amplified using sets of med consent to participate. Control individuals were amplimeres of no more than 600 bp that overlapped by group matched to cases for age, sex, and ethnicity from no less than 50 bp. All PCRs were performed on MJ more than 1400 blood donors recruited from the local thermocyclers in a volume of 24 ␮l containing 40 ng of branch of the National Blood Transfusion Service genomic DNA, 10 pmol of each primer, 100 ␮M dNTPs, (Wales). and 0.5 units of Hotstar Taq Polymerase (Quiagen, UK) with a standard touchdown protocol previously Results described.14 Genomic regions that proved particularly difficult to amplify due to their high GC content were cDNA and genomic structure amplified in a volume of 50 ␮l using a GC-Rich PCR According to the published data, GRIN1 has 21 kit (Roche) using reaction and cycling conditions exons.11 Exons 1 and 21 were reported to span 258 and according to the manufacturer’s instructions. Details of 186 bp respectively but this does not include 1093 the primer sequences and PCR conditions can be bases of 5Ј UTR and 1227 bases of 3Ј UTR. With the obtained from our web site (http://psychmed.uwcm. inclusion of UTR sequences, we conclude that exons 1 ac.uk/psychosis/ publications/nmda.html). and 21 actually span 1351 and 1344 bases respectively. We were unable
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