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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

Molecular Psychiatry volume 6, pages 274–284 (2001)Cite this article

Abstract

Glutamatergic dysregulation has been hypothesized to play a role in schizophrenia. The N-methyl-D-aspartate (NMDA) type of glutamate receptor especially is of interest because, in addition to binding sites for glutamate and glycine, a necessary co-agonist, this receptor also contains noncompetitive binding sites for the psychotomimetics phencyclidine (PCP), MK-801, and ketamine. PCP-induced psychosis has been a useful disease model in that both the positive as well as the negative symptomatologies seen in schizophrenia are observed. Recently, a mouse deficient in expression of the NR1 subunit gene (NMDAR1) of the heteromeric receptor has been developed and shown to display aberrant behaviors, with reduced social and sexual interactions as well as increased stereotypic motor activity. In an extensive examination of the NMDAR1 gene in our laboratory in approximately 100 chronic schizophrenic patients, 28 unique sequence changes were identified, including eight single nucleotide polymorphisms (SNPs) in the 5′ untranslated region (5′UTR), six SNPs in coding regions (cSNPs), eleven intronic SNPs, two intronic deletions of 7 and 30 bp, and an intronic microinsertion/deletion. With the exception of one previously reported cSNP, all of the identified changes were novel. The frequency of polymorphisms differed significantly by ethnicity and several appeared to be in linkage disequilibrium. None of the changes appeared likely to be of functional significance, thus suggesting that changes in the genomic NMDAR1 are unlikely to contribute to the etiology of schizophrenia. Estimates of nucleotide diversity are comparable to those observed in studies of other genes.

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Acknowledgements

This work was supported in part by grants from the National Alliance for Research on Schizophrenia and Depression (NARSAD), the National Institute of Mental Health (MH54232), and the Beckman Research Institute at the City of Hope National Medical Center. We graciously thank all research participants and acknowledge the support and cooperation of staff from the Mayo Clinic (MN), Zumbro Valley Mental Health Center (MN), St Peter Regional Treatment Center (MN), Anoka-Metro Regional Treatment Center (MN), Western and Eastern State Hospitals (WA), and Dammasch State Hospital (OR).

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Authors and Affiliations

  1. Division of Molecular Medicine, City of Hope National Medical Center, Duarte, CA, USA

    S R Rice, N Niu, D B Berman & J L Sobell

  2. Department of Psychiatry, University of Washington, Seattle, WA, USA

    L L Heston

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  1. S R Rice
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  2. N Niu
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  4. L L Heston
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Rice, S., Niu, N., Berman, D. et al. 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 6, 274–284 (2001). https://doi.org/10.1038/sj.mp.4000838

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