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Mutation analysis of the NMDAR2B (GRIN2B) gene in schizophrenia

Molecular Psychiatry volume 6, pages 211–216 (2001)Cite this article

Abstract

NMDA receptor dysfunction may be involved in the pathophysiology of schizophrenia. Based on this hypothesis, we screened 48 Japanese patients with schizophrenia for mutations in the coding region of the NMDAR2B subunit gene (GRIN2B). An association study between the identified DNA sequence variants and schizophrenia was performed in 268 Japanese patients with schizophrenia and 337 Japanese control subjects. Eight single nucleotide polymorphisms were detected, all of which were synonymous. The association sample showed statistically significant excesses of homozygosity for the polymorphisms in the 3’ region of the last exon in the patients with schizophrenia (P = 0.004) and higher frequency of the G allele of the 366C/G polymorphism (corrected P = 0.04) in the patients than in the controls. Although we did not detect NMDAR2B protein variants, our findings support the possibility that the GRIN2B gene or a locus in linkage disequilibrium with it may confer susceptibility to schizophrenia. Replication studies in independent samples are warranted.

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References

  1. Luby ED, Ccohen BD, Rosenbaum F, Gottlieb J, Kelley R . Study of a new schizophrenomimetic drug, Sernyl Arch Neurol Psychiatry 1959 81: 363–369

    Article  CAS  Google Scholar 

  2. Javitt DC, Zukin SR . Recent advances in the phencyclidine model of schizophrenia Am J Psychiatry 1991 148: 1301–1308

    Article  CAS  Google Scholar 

  3. Ellison G . The N-methyl-D-aspartate antagonists phencyclidine, ketamine and dizocilpine as both behavioral and anatomical models of the dementias Brain Res Brain Res Rev 1995 20: 250–267

    Article  CAS  Google Scholar 

  4. Malhotra AK, Pinals DA, Adler CM, Elman I, Clifton A, Pickar D et al. Ketamine-induced exacerbation of psychotic symptoms and cognitive impairment in neuroleptic-free schizophrenics Neuropsychopharmacology 1997 17: 141–150

    Article  CAS  Google Scholar 

  5. Abi-Saab WM, D'Souza DC, Moghaddam B, Krystal JH . The NMDA antagonist model for schizophrenia: promise and pitfalls Pharmacopsychiatry 1998 31 Suppl 2: 104–109

    Article  CAS  Google Scholar 

  6. Nakanishi S, Nakajima Y, Masu M, Ueda Y, Nakahara K, Watanabe D et al. Glutamate receptors: brain function and signal transduction Brain Res Brain Res Rev 1998 26: 230–235

    Article  Google Scholar 

  7. Kutsuwada T, Kashiwabuchi N, Mori H, Sakimura K, Kushiya E, Araki K et al. Molecular diversity of the NMDA receptor channel Nature 1992 358: 36–41

    Article  CAS  Google Scholar 

  8. Monyer H, Sprengel R, Schoepfer R, Herb A, Higuchi M, Lomeli H et al. Heteromeric NMDA receptors: molecular and functional distinction of subtypes Science 1992 256: 1217–1221

    Article  CAS  Google Scholar 

  9. Forrest D, Yuzaki M, Soares HD, Ng L, Luk DC, Sheng M et al. Targeted disruption of NMDA receptor 1 gene abolishes NMDA response and results in neonatal death Neuron 1994 13: 325–338

    Article  CAS  Google Scholar 

  10. Li Y, Erzurumlu RS, Chen C, Jhaveri S, Tonegawa S . Whisker-related neuronal patterns fail to develop in the trigeminal brainstem nuclei of NMDAR1 knockout mice Cell 1994 76: 427–437

    Article  CAS  Google Scholar 

  11. Ikeda K, Araki K, Takayama C, Inoue Y, Yagi T, Aizawa S, Mishina M . Reduced spontaneous activity of mice defective in the epsilon 4 subunit of the NMDA receptor channel Brain Res Mol Brain Res 1995 33: 61–71

    Article  CAS  Google Scholar 

  12. Sakimura K, Kutsuwada T, Ito I, Manabe T, Takayama C, Kushiya E et al. Reduced hippocampal LTP and spatial learning in mice lacking NMDA receptor epsilon 1 subunit Nature 1995 373: 151–155

    Article  CAS  Google Scholar 

  13. Ebralidze AK, Rossi DJ, Tonegawa S, Slater NT . Modification of NMDA receptor channels and synaptic transmission by targeted disruption of the NR2C gene J Neurosci 1996 16: 5014–5025

    Article  CAS  Google Scholar 

  14. Kutsuwada T, Sakimura K, Manabe T, Takayama C, Katakura N, Kushiya E et al. Impairment of suckling response, trigeminal neuronal pattern formation, and hippocampal LTD in NMDA receptor epsilon 2 subunit mutant mice Neuron 1996 16: 333–344

    Article  CAS  Google Scholar 

  15. Das S, Sasaki YF, Rothe T, Premkumar LS, Takasu M, Crandall JE et al. Increased NMDA current and spine density in mice lacking the NMDA receptor subunit NR3A Nature 1998 393: 377–381

    Article  CAS  Google Scholar 

  16. Mohn AR, Gainetdinov RR, Caron MG, Koller BH . Mice with reduced NMDA receptor expression display behaviors related to schizophrenia Cell 1999 98: 427–436

    Article  CAS  Google Scholar 

  17. Kutsuwada T, Kashiwabuchi N, Mori H, Sakimura K, Kushiya E, Araki K et al. Molecular diversity of the NMDA receptor channel Nature 1992 358: 36–41

    Article  CAS  Google Scholar 

  18. Watanabe M, Inoue Y, Sakimura K, Mishina M . Developmental changes in distribution of NMDA receptor channel subunit mRNAs Neuroreport 1992 3: 1138–1140

    Article  CAS  Google Scholar 

  19. Standaert DG, Testa CM, Young AB, Penney JB, Jr . Organization of N-methyl-D-aspartate glutamate receptor gene expression in the basal ganglia of the rat J Comp Neurol 1994 343: 1–16

    Article  CAS  Google Scholar 

  20. Kayadjanian N, Heavens RP, Besson MJ, Sirinathsinghji DJ . Striatal NMDAR2B mRNA expression after bilateral cortical and unilateral nigral deafferentation Neuroreport 1996 7: 713–716

    Article  CAS  Google Scholar 

  21. Rudolf GD, Cronin CA, Landwehrmeyer GB, Standaert DG, Penney JB, Jr, Young AB . Expression of N-methyl-D-aspartate glutamate receptor subunits in the prefrontal cortex of the rat Neuroscience 1996 73: 417–427

    Article  CAS  Google Scholar 

  22. Toyoda H, Takahata R, Inayama Y, Sakai J, Matsumura H, Yoneda H et al. Effect of antipsychotic drugs on the gene expression of NMDA receptor subunits in rats Neurochem Res 1997 22: 249–252

    Article  CAS  Google Scholar 

  23. Chen AC, McDonald B, Moss SJ, Gurling HM . Gene expression studies of mRNAs encoding the NMDA receptor subunits NMDAR1, NMDAR2A, NMDAR2B, NMDAR2C, and NMDAR2D following long-term treatment with cis- and trans-flupenthixol as a model for understanding the mode of action of schizophrenia drug treatment Brain Res Mol Brain Res 1998 54: 92–100

    Article  Google Scholar 

  24. Oretti RG, Spurlock G, Buckland PR, McGuffin P . Lack of effect of antipsychotic and antidepressant drugs on glutamate receptor mRNA levels in rat brains Neurosci Lett 1994 177: 39–43

    Article  CAS  Google Scholar 

  25. Riva MA, Tascedda F, Lovati E, Racagni G . Regulation of NMDA receptor subunit messenger RNA levels in the rat brain following acute and chronic exposure to antipsychotic drugs Brain Res Mol Brain Res 1997 50: 136–142

    Article  CAS  Google Scholar 

  26. Williams NM, Rees MI, Holmans P, Norton N, Cardno AG, Jones LA et al. A two-stage genome scan for schizophrenia susceptibility genes in 196 affected sibling pairs Hum Mol Genet 1999 8: 1729–1739

    Article  CAS  Google Scholar 

  27. Dawson E, Powell JF, Sham P, Shaikh S, Taylor C, Clements A et al. Systematic search for major genes in schizophrenia: methodological issues and results from chromosome 12 Am J Med Genet 1995 60: 424–433

    Article  CAS  Google Scholar 

  28. Shaw SH, Kelly M, Smith AB, Shields G, Hopkins PJ, Loftus J et al. A genomewide search for schizophrenia susceptibility genes Am J Med Genet 1998 81: 364–376

    Article  CAS  Google Scholar 

  29. Riley BP, Tahir E, Rajagopalan S, Mogudi-Carter M, Faure S, Weissenbach J et al. A linkage study of the N-methyl-D-aspartate receptor subunit gene loci and schizophrenia in southern African Bantu-speaking families Psychiatr Genet 1997 7: 57–74

    Article  CAS  Google Scholar 

  30. Faraone SV, Matise T, Svrakic D, Pepple J, Malaspina D, Suarez B et al. Genome scan of European-American schizophrenia pedigrees: results of the NIMH Genetics Initiative and Millennium Consortium Am J Med Genet 1998 81: 290–295

    Article  CAS  Google Scholar 

  31. Spurlock G, Williams J, McGuffin P, Aschauer HN, Lenzinger E, Fuchs K et al. European Multicentre Association Study of Schizophrenia: a study of the DRD2 Ser311 Cys and DRD3 Ser9Gly polymorphisms Am J Med Genet 1998 81: 24–28

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Drs M Itokawa, J Aoki, H Shibuya, Y Okubo, A Iwawaki, K Ota for recruiting the subjects. This study was supported by the Research Grants for Nervous and Mental Disorders from the Ministry of Health and Welfare of Japan, and by Grant-in-Aid for Scientific Research, Ministry of Education, Japan.

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Authors and Affiliations

  1. Department of Medical Genetics, Institute of Basic Medical Sciences, University of Tsukuba, Ibaraki, 305–8575, Japan

    T Ohtsuki, K Sakurai, H Dou, K Yamakawa-Kobayashi & T Arinami

  2. Department of Neuropsychiatry, Tokyo Medical and Dental University School of Medicine, Tokyo, 113–8519, Japan

    M Toru

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  1. T Ohtsuki
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  2. K Sakurai
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Correspondence to T Arinami.

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Ohtsuki, T., Sakurai, K., Dou, H. et al. Mutation analysis of the NMDAR2B (GRIN2B) gene in schizophrenia. Mol Psychiatry 6, 211–216 (2001). https://doi.org/10.1038/sj.mp.4000808

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