A Genetic Variant of the Serine Racemase Gene Is Associated with Schizophrenia


      Serine racemase (SRR) is a brain-enriched enzyme that converts l-serine to d-serine, which acts as an endogenous ligand of N-methyl d-aspartate (NMDA) receptors. Dysfunction of SRR may reduce the function of NMDA receptors and susceptibility to schizophrenia.


      We genotyped three single-nucleotide polymorphisms (SNPs) of the 5′ region of the SRR gene in 525 patients with schizophrenia and 524 healthy controls. Effects of SNPs on the promoter activity and on serum levels of total and d-serine were examined.


      We found a significant excess of the IVS1a+465C allele of the SRR gene in schizophrenia, especially in the paranoid subtype (p = .0028). A reporter assay showed that the IVS1a+465C allele had 60% lower promoter activity than did the IVS1a+465G allele.


      The IVS1a+465C allele of the SRR gene, which reduces expression of the gene, is a risk factor for schizophrenia, especially the paranoid subtype.

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        • Chatterton J.E.
        • Awobuluyi M.
        • Premkumar L.S.
        • Takahashi H.
        • Talantova M.
        • Shin Y.
        • et al.
        Excitatory glycine receptors containing the NR3 family of NMDA receptor subunits.
        Nature. 2002; 415: 793-798
        • Das S.
        • Sasaki Y.F.
        • Rothe T.
        • Premkumar L.S.
        • Takasu M.
        • Crandall J.E.
        • et al.
        Increased NMDA current and spine density in mice lacking the NMDA receptor subunit NR3A.
        Nature. 1998; 393: 377-381
        • De Miranda J.
        • Santoro A.
        • Engelender S.
        • Wolosker H.
        Human serine racemase: Moleular cloning, genomic organization and functional analysis.
        Gene. 2000; 256: 183-188
        • Goltsov A.Y.
        • Loseva J.G.
        • Andreeva T.V.
        • Grigorenko A.P.
        • Abramova L.I.
        • Kaleda V.G.
        • et al.
        Polymorphism in the 5′-promoter region of serine racemase gene in schizophrenia.
        Mol Psychiatry. 2006; 11: 325-326
        • Hashimoto Y.
        • Omae F.
        • Furukawa S.
        Reduction of NGF protein level in rat dorsal hippocampus following administration of kainic acid.
        Neurosci Lett. 1992; 140: 203-205
        • Jackson M.E.
        • Homayoun H.
        • Moghaddam B.
        NMDA receptor hypofunction produces concomitant firing rate potentiation and burst activity reduction in the prefrontal cortex.
        Proc Natl Acad Sci U S A. 2004; 101: 8467-8472
        • Morikawa A.
        • Hamase K.
        • Inoue T.
        • Konno R.
        • Niwa A.
        • Zaitsu K.
        Determination of free D-aspartic acid, D-serine and D-alanine in the brain of mutant mice lacking D-amino acid oxidase activity.
        J Chromatogr B Biomed Sci Appl. 2001; 757: 119-125
        • Morris R.G.
        • Anderson E.
        • Lynch G.S.
        • Baudry M.
        Selective impairment of learning and blockade of long-term potentiation by an N-methyl-D-aspartate receptor antagonist, AP5.
        Nature. 1986; 319: 774-776
        • Muller D.
        • Joly M.
        • Lynch G.
        Contributions of quisqualate and NMDA receptors to the induction and expression of LTP.
        Science. 1988; 242: 1694-1697
        • Olney J.W.
        • Farber N.B.
        Glutamate receptor dysfunction and schizophrenia.
        Arch Gen Psychiatry. 1995; 52: 998-1007
        • Olney J.W.
        • Ikonomidou C.
        • Mosinger J.L.
        • Frierdich G.
        MK-801 prevents hypobaric-ischemic neuronal degeneration in infant rat brain.
        J Neurosci. 1989; 9: 1701-1704
        • Olney J.W.
        • Labruyere J.
        • Wang G.
        • Wozniak D.F.
        • Price M.T.
        • Sesma M.A.
        NMDA antagonist neurotoxicity: Mechanism and prevention.
        Science. 1991; 254: 1515-1518
        • Panizzutti R.
        • De Miranda J.
        • Ribeiro C.S.
        • Engelender S.
        • Wolosker H.
        A new strategy to decrease N-methyl-D-aspartate (NMDA) receptor coactivation: Inhibition of D-serine synthesis by converting serine racemase into an eliminase.
        Proc Natl Acad Sci U S A. 2001; 98: 5294-5299
        • Qin S.
        • Zhao X.
        • Pan Y.
        • Liu J.
        • Feng G.
        • Fu J.
        • et al.
        An association study of the N-methyl-D-aspartate receptor NR1 subunit gene (GRIN1) and NR2B subunit gene (GRIN2B) in schizophrenia with universal DNA microarray.
        Eur J Hum Genet. 2005; 13: 807-814
        • Wolosker H.
        • Blackshaw S.
        • Snyder S.H.
        Serine racemase: A glial enzyme synthesizing D-serine to regulate glutamate-N-methyl-D-aspartate neurotransmission.
        Proc Natl Acad Sci U S A. 1999; 96: 13409-13414
        • Xia M.
        • Liu Y.
        • Figueroa D.J.
        • Chiu C.S.
        • Wei N.
        • Lawlor A.M.
        • et al.
        Characterization and localization of a human serine racemase.
        Brain Res Mol Brain Res. 2004; 125: 96-104
        • Wolosker H.
        • Sheth K.N.
        • Takahashi M.
        • Mothet J.P.
        • Brady Jr, R.O.
        • Ferris C.D.
        • Snyder S.H.
        Purification of serine racemase: Biosynthesis of the neuromodulator D-serine.
        Proc Natl Acad Sci U S A. 1999; 96: 721-725
        • Yamada K.
        • Ohnishi T.
        • Hashimoto K.
        • Ohba H.
        • Iwayama-Shigeno Y.
        • Toyoshima M.
        • et al.
        Identification of multiple serine racemase (SRR) mRNA isoforms and genetic analyses of SRR and DAO in schizophrenia and d-serine levels.
        Biol Psychiatry. 2005; 57: 1493-1503
        • Zhao X.
        • Li H.
        • Shi Y.
        • Tang R.
        • Chen W.
        • Liu J.
        • et al.
        Significant association between the genetic variations in the 5′ end of the N-methyl-D-aspartate receptor subunit gene GRIN1 and schizophrenia.
        Biol Psychiatry. 2006; 59: 747-753