Identification of Multiple Serine Racemase (SRR) mRNA Isoforms and Genetic Analyses of SRR and DAO in Schizophrenia and d-Serine Levels

Yamada, Kazuo; Ohnishi, Tetsuo; Hashimoto, Kenji; Ohba, Hideki; Iwayama-Shigeno, Yoshimi; Toyoshima, Manabu; Okuno, Akira; Takao, Hitomi; Toyota, Tomoko; Minabe, Yoshio; Nakamura, Kazuhiko; Shimizu, Eiji; Itokawa, Masanari; Mori, Norio; Iyo, Masaomi; Yoshikawa, Takeo

doi:10.1016/j.biopsych.2005.03.018

Cited by 135 publications

(89 citation statements)

References 43 publications

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“…The SRR protein was purified a decade ago (Wolosker et al 1999) and shown to convert L-serine to D-serine, the endogenous ligand of the glycine site of NMDA receptors in the brain, and since then the focus has been on its association to neurological disorders (Yamada et al 2005;Morita et al 2007). However, certain subunits of NMDA receptors are known to be expressed in osteoblasts and chondrocytes (Chenu et al 1998;Laketic-Ljubojevic et al 1999;Hinoi et al 2003), and recently it was shown that SRR negatively regulates chondrocyte differentiation Where a proxy SNP is not presented, the GWAS SNP corresponded to the strongest association.…”

Section: Discussionmentioning

confidence: 99%

Population genomics in a disease targeted primary cell model

Grundberg

Kwan²,

Ge³

et al. 2009

Genome Res.

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The common genetic variants associated with complex traits typically lie in noncoding DNA and may alter gene regulation in a cell type-specific manner. Consequently, the choice of tissue or cell model in the dissection of disease associations is important. We carried out an expression quantitative trait loci (eQTL) study of primary human osteoblasts (HOb) derived from 95 unrelated donors of Swedish origin, each represented by two independently derived primary lines to provide biological replication. We combined our data with publicly available information from a genome-wide association study (GWAS) of bone mineral density (BMD). The top 2000 BMD-associated SNPs (P < ;10 À3 ) were tested for cisassociation of gene expression in HObs and in lymphoblastoid cell lines (LCLs) using publicly available data and showed that HObs have a significantly greater enrichment (threefold) of converging cis-eQTLs as compared to LCLs. The top 10 BMD loci with SNPs showing strong cis-effects on gene expression in HObs (P = 6 3 10 À10 À 7 3 10 À16 ) were selected for further validation using a staged design in two cohorts of Caucasian male subjects. All 10 variants were tested in the Swedish MrOS Cohort (n = 3014), providing evidence for two novel BMD loci (SRR and MSH3). These variants were then tested in the Rotterdam Study (n = 2090), yielding converging evidence for BMD association at the 17p13.3 SRR locus (P combined = 5.6 3 10 À5 ). The cis-regulatory effect was further fine-mapped to the proximal promoter of the SRR gene (rs3744270, r 2 = 0.5, P = 2.6 3 10 À15 ). Our results suggest that primary cells relevant to disease phenotypes complement traditional approaches for prioritization and validation of GWAS hits for follow-up studies.

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Section: Discussionmentioning

confidence: 99%

Population genomics in a disease targeted primary cell model

Grundberg

Kwan²,

Ge³

et al. 2009

Genome Res.

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“…The first consisted of 124 nuclear families (376 members, of whom 163 were affected) for a family-based association test. The details of this sample are described elsewhere (46). The second set was an independent case-control sample panel, which comprised 570 unrelated schizophrenics (285 males and 285 females; mean Ϯ SD age, 47.0 Ϯ 11.4 years), and 570 age-and sex-matched controls who showed no history of mental illness in a brief psychiatric interview or structured interview by experts (285 males and 285 females; mean Ϯ SD age, 46.7 Ϯ 11.1 years).…”

Section: Methodsmentioning

confidence: 99%

Genetic analysis of the calcineurin pathway identifies members of the EGR gene family, specifically EGR3 , as potential susceptibility candidates in schizophrenia

Yamada¹,

Gerber

Iwayama³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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129

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The calcineurin cascade is central to neuronal signal transduction, and genes in this network are intriguing candidate schizophrenia susceptibility genes. To replicate and extend our previously reported association between the PPP3CC gene, encoding the calcineurin catalytic ␥-subunit, and schizophrenia, we examined 84 SNPs from 14 calcineurin-related candidate genes for genetic association by using 124 Japanese schizophrenic pedigrees. Four of these genes (PPP3CC, EGR2, EGR3, and EGR4) showed nominally significant association with schizophrenia. In a postmortem brain study, EGR1, EGR2, and EGR3 transcripts were shown to be downregulated in the prefrontal cortex of schizophrenic, but not bipolar, patients. These findings raise a potentially important role for EGR genes in schizophrenia pathogenesis. Because EGR3 is an attractive candidate gene based on its chromosomal location close to PPP3CC within 8p21.3 and its functional link to dopamine, glutamate, and neuregulin signaling, we extended our analysis by resequencing the entire EGR3 genomic interval and detected 15 SNPs. One of these, IVS1 ؉ 607A3 G SNP, displayed the strongest evidence for disease association, which was confirmed in 1,140 independent case-control samples. An in vitro promoter assay detected a possible expression-regulatory effect of this SNP. These findings support the previous genetic association of altered calcineurin signaling with schizophrenia pathogenesis and identify EGR3 as a compelling susceptibility gene.genetic association ͉ immediate early gene ͉ postmortem brain ͉ enhancer

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“…[21][22][23][24][25][26][27] We have explored a role for D-serine synthesis in SZ. As the gene for SR itself is located to chromosome 17, which has been neither linked to nor associated with SZ, 28 we focused on binding partners for SR with some relationship to SZ. Here, we report binding of SR to protein interacting with C-kinase (PICK1), whose gene is located at chromosome 22q13.1.…”

Section: Introductionmentioning

confidence: 99%

Serine racemase binds to PICK1: potential relevance to schizophrenia

et al. 2005

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Accumulating evidence from both genetic and clinico-pharmacological studies suggests that D-serine, an endogenous coagonist to the NMDA subtype glutamate receptor, may be implicated in schizophrenia (SZ). Although an association of genes for D-serine degradation, such as D-amino acid oxidase and G72, has been reported, a role for D-serine in SZ has been unclear. In this study, we identify and characterize protein interacting with C-kinase (PICK1) as a protein interactor of the D-serine synthesizing enzyme, serine racemase (SR). The binding of endogenous PICK1 and SR requires the PDZ domain of PICK1. The gene coding for PICK1 is located at chromosome 22q13, a region frequently linked to SZ. In a case-control association study using well-characterized Japanese subjects, we observe an association of the PICK1 gene with SZ, which is more prominent in disorganized SZ. Our findings implicating PICK1 as a susceptibility gene for SZ are consistent with a role for D-serine in the disease.

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Identification of Multiple Serine Racemase (SRR) mRNA Isoforms and Genetic Analyses of SRR and DAO in Schizophrenia and d-Serine Levels

Cited by 135 publications

References 43 publications

Population genomics in a disease targeted primary cell model

Population genomics in a disease targeted primary cell model

Genetic analysis of the calcineurin pathway identifies members of the EGR gene family, specifically EGR3 , as potential susceptibility candidates in schizophrenia

Serine racemase binds to PICK1: potential relevance to schizophrenia

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