Abstract
The glutamatergic system is the major excitatory neurotransmitter system in the CNS. Glutamate 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.
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References
Hollmann M, Heinemann S . Cloned glutamate receptors Annu Rev Neurosci 1994 17: 31–108
Pin J-P, Duvoisin R . Review: neurotransmitter receptors I. The metabotropic glutamate receptors: structure and functions Neuropharmacology 1995 34: 1–26
Seeburg PH, Higuchi M, Sprengel R . RNA editing of brain glutamate receptor channels: mechanism and physiology Brain Res Rev 1998 26: 217–229
Sugiura N, Patel RG, Corriveau RA . N-methyl-D-aspartate receptors regulate a group of transiently expressed genes in the developing brain J Biol Chem 2001 276: 14257–14263
Constantine-Paton M, Cline HT . LTP and activity-dependent synaptogenesis: the more alike they are, the more different they become Curr Opin Neurobiol 1998 8: 139–148
Cull-Candy S, Brickley S, Farrant M . NMDA receptor subunits: diversity, development and disease Curr Opin Neurobiol 2001 11: 327–335
Tsien JZ, Huerta PT, Tonegawa S . The essential role of hippocampal CA1 NMDA receptor-dependent synaptic plasticity in spatial memory Cell 1996 87: 1327–1338
McHugh TJ, Blum KI, Tsien JZ, Tonegawa S, Wilson MA . Impaired hippocampal representation of space in CA1-specific NMDAR1 knockout mice Cell 1996 87: 1339–1349
Mohn AR, Gainetdinov RR, Caron MG, Koller BH . Mice with reduced NMDA receptor expression display behaviours related to schizophrenia Cell 1999 98: 427–436
Moriyoshi K, Masu M, Ishii T, Shigemoto R, Mizuno N, Nakanishi S . Molecular cloning and characterization of the rat NMDA receptor Nature 1991 353: 31–37
Zimmer M, Fink TM, Franke Y, Lichter P, Spiess J . Cloning and structure of the gene encoding the human N-methyl-D-aspartate receptor (NMDAR1) Gene 1995 159: 219–223
Altschul SF, Madden TL, Schäffer AA, Zhang J, Zhang Z, Webb M et al. Gapped BLAST and PSI-BLAST: a new generation of protein database search programs Nucl Acids Res 1997 25: 3389–3402
Tatusova TA, Madden TL . Blast 2 sequences — a new tool for comparing protein and nucleotide sequences FEMS Microbiol Lett 1999 174: 247–250
Austin J, Hoogendoorn B, Buckland P, Speight G, Cardno A, Bowen T et al. Comparative sequencing of the proneurotensin gene and association studies in schizophrenia Mol Psychiatry 2000 5: 208–212
Jones AC, Austin J, Hansen N, Hoogendoorn B, Oefner PJ, Cheadle JP et al. Optimal temperature selection for mutation detection by denaturing HPLC and comparison to single-stranded conformation polymorphism and heteroduplex analysis Clin Chem 1999 45: 1133–1140
O'Donovan MC, Oefner PJ, Roberts SC, Austin J, Hoogendoorn B, Guy C et al. Blind analysis of denaturing high performance liquid chromatography as a tool for mutation detection Genomics 1998 52: 44–49
Hoogendoorn B, Norton N, Kirov G, Williams N, Hamshere ML, Spurlock G et al. Cheap, accurate and rapid allele frequency estimation of single nucleotide polymorphisms by primer extension and DHPLC in DNA pools Hum Genet 2000 107: 488–493
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th edn American Psychiatric Association: Washington DC 1994
McGuffin P, Farmer AE, Harvey I . A polydiagnostic application of operational criteria in studies of psychotic illness: development and reliability of the OPCRIT system Arch Gen Psychiatry 1992 48: 643–647
Wing JK, Cooper JE, Satorius N . The Measurement and Classification of Psychiatric Illness Cambridge University Press: Cambridge 1974
Wing JK, Babor T, Brugha T . SCAN: schedules for the clinical assessment in neuropsychiatry Arch Gen Psychiatry 1990 47: 589–593
Ohtsuki T, Sakurai K, Dou H, Toru M, Yamakawa-Kobayashi K, Arinami T . Mutation analysis of the NMDAR2B (GRIN2B) gene in schizophrenia Mol Psychiatry 2001 6: 211–216
Cargill M, Altshuler D, Ireland J, Sklar P, Ardlie K, Patil N et al. Characterization of single-nucleotide polymorphisms in coding regions of human genes Nature Genet 1999 22: 231–238
Halushka MK, Fan J-B, Bentley K, Hsie L, Shen N, Weder A et al. Patterns of single-nucleotide polymorphisms in candidate genes for blood-pressure homeostasis Nature Genet 1999 22: 239–247
Rice SR, Niu N, Berman DB, Heston LL, Sobell JL . Identification of single nucleotide polymorphisms (SNPs) and other sequence changes and estimation of nucleotide diversity in coding and flanking regions of the NMDAR1 receptor gene in schizophrenic patients Mol Psychiatry 2001 6: 274–284
Marth G, Yeh R, Minton M, Donaldson R, Li Q, Duan S et al. Single-nucleotide polymorphisms in the public domain: how useful are they? Nature Genet 2001 27: 371–372
Reich DE, Lander ES . On the allelic spectrum of human disease Trends in Genetics 2001 17: 502–510
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This study was supported by the MRC (UK).
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Williams, N., Bowen, T., Spurlock, G. et al. Determination of the genomic structure and mutation screening in schizophrenic individuals for five subunits of the N-methyl-D-aspartate glutamate receptor. Mol Psychiatry 7, 508–514 (2002). https://doi.org/10.1038/sj.mp.4001030
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DOI: https://doi.org/10.1038/sj.mp.4001030
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