Entrez Gene Links

General Function and protein/protein interactions

Chromosomal location and linkage evidence for this region

Positive association evidence 

Expression changes

Table 1: Genes controlling glutamate receptor agonist availability

DAO D-amino acid oxidase

OMIM GeneCards

Metabolises the NMDA receptor glycine site agonist D-serine (Chumakov et al., 2002)

12q24 MIM 181500

Associated in Chinese, French, German Israeli and Scottish case studies(Chumakov et al., 2002)(Korostishevsky et al., 2004;Liu et al., 2004;Ma et al., 2006;Schumacher et al., 2004)  PUBMED

Plasma D-serine levels are decreased. L-serine levels are elevated (Hashimoto et al., 2003). In neuroleptic free patients, plasma glycine levels are decreased and total serine (D + L)  increased (Sumiyoshi et al., 2004). Increased DAO activity in cerebellum ( Kapoor et al 2006)

DAOA D-amino acid oxidase activator OMIM

GeneCards

Activates DAO (Chumakov et al., 2002)

13q33.2 SCZD713q32-q34 reviewed by (O'Donovan et al., 2003)

Associated in American, Chinese, French, German and Israeli case studies (Addington et al., 2004;Chumakov et al., 2002;Korostishevsky et al., 2004;Schumacher et al., 2004;Wang et al., 2004). .PUBMED

See above

Converts L-serine to D-Serine: Binds to PICK1 (Fujii et al., 2005

)

Association reported in a Japanese study Morita et al, 2006 

MTHFR Methylenetetrahydrofolate reductase OMIM 607093 GeneCards

Controls homocysteine metabolism: Homocysteine stimulates the NMDA receptor via an action at the glutamate binding site but inhibits NMDA effects via an antagonist effect at the glycine binding site (Lipton et al., 1997). 

1p36.3 Cited in Genome scan meta-analysis (Lewis et al., 2003)

Significant association reported in a meta-analysis of 10 case studies (Muntjewerff et al., 2005). PUBMED Homocysteine and NMDA

Reduced activity of the enzyme associated with the polymorphism seen in schizophrenia is associated with elevated plasma levels of homocysteine (Muntjewerff et al., 2005)

NAALAD2 N-acetylated alpha-linked acidic dipeptidase 2 GeneCards

Hydrolyses N-acetylaspartylglutamate (NAAG) to glutamate and N-acetyl aspartate. NAAG is both a metabotropic receptor agonist (GRM3) and an NMDA receptor partial agonist (Coyle, 1997)

11q14.3-q21 (OMIM_SCZD2, 2005)

Situated at the chromosome 11 breakpoint of the chromosome1/11 translocation reported to associate with schizophrenia (Semple et al., 2001) PUBMED

Decreased activity in HPC and PFC (Weatherspoon et al., 1996): Increased levels of NAAG (Tsai et al., 1995). No difference in NAA concentrations in frontal cortex in life but a negative correlation between NAA levels and symptomatology (Gohla et al., 1998)

Association reported in Askenazi Jewish families (Fallin et al., 2005) 
PUBMED

PRODH Proline dehydrogenase

OMIM 606810 GeneCards

Proline can be a precursor for glutamate via PRODH

(Thompson et al., 1985). 

22q11.21 SCZD4

Association reported in American Chinese and French family studies  (Li et al., 2004a;Liu et al., 2002a),(Jacquet et al., 2002).  PUBMED

Normal mRNA in dorsolateral prefrontal cortex (Tunbridge et al., 2004). Reduced PRODH activity in schizophrenic patients with alleles or deletions found in schizophrenia (Bender et al., 2005;Jacquet et al., 2002). Hyperprolinemia is a risk factor for psychosis (Jacquet et al., 2005)

SLC1A2 solute carrier family 1 (glial high affinity glutamate transporter), member 2 OMIM 600300 GeneCards

Glutamate and cysteine transporter
Expression in astrocytes positively modulated by GRM3 and negatively modulated by GRM5 Aronica et al, 2003. Expression increased by BDNF  (Rodriguez-kern et al, 2003) and by AKT1 in astrocytes (Li et al,2006) 

11p13-p12 Linkage reported in an American study (Suarez et al, 2006

Association reported in a Japanese case study (Deng et al., 2004b). PUBMED

Increased prefrontal cortex mRNA expression in neuroleptic free patients: Normal or reduced in medicated patients (Matute et al., 2005) Reduced mRNA expression in prefrontal cortex (Ohnuma et al., 1998a) (Egan et al., 2004)and hippocampus (Ohnuma et al., 2000) Increased expression in thalamus (Smith et al., 2001)

Table 2: Genes controlling glutamate packaging and release and presynaptic function

NOSIAP (CAPON) (also postsynaptic)  OMIM 605551 GeneCards

Binds to NOS1 and synapsins (SYN1, SYN2, SYN3)

1q23.3 MIM 181500

Linked in American family and associated in Columbian and Chinese case studies (Brzustowicz et al., 2004;Miranda et al., 2005;Zheng et al., 2005) PUBMED

Increased mRNA expression in dorsolateral prefrontal cortex (Xu et al., 2005)

CPLX2  Complexin II OMIM 605033 GeneCards

Syntaxin binding protein involved in synaptic vesicle exocytosis

5q35.2: 5q31-q35 described as a susceptibility locus in portugese families (Sklar et al., 2004) 

Association reported in a Korean case study (Lee et al., 2005).PUBMED

Reduced hippocampal (Sawada et al., 2005)but not prefrontal (Sawada et al., 2002)or anterior cingulate cortex (Eastwood and Harrison, 2001) protein levels . Reduced mRNA in prefrontal and superior temporal cortex (Eastwood and Harrison, 2005). Reduced cerebellar mRNA and protein (Eastwood et al., 2001)

DTNBP1 Dysbindin OMIM 607145 GeneCards

Positively regulates glutamate release and upregulates the expression 
of presynaptic proteins SYN1, SNAP25 (Numakawa et al., 2004). Also part of the biogenesis of organelles complex involved in endosome to lysosome transport. Dysbindin or MUTED knockdown blocks D2 dopamine receptor (DRD2) internalisation, increasing cell surface expression Iizuka et al, 2007

6p22.3 SCZD3 MIM 600511

Association reported in multiple case and family studies (Straub et al., 2002;Tang et al., 2003b;van den Oord et al., 2003;Van Den et al., 2003;Williams et al., 2004a). PUBMED

Decreased protein levels in presynaptic glutamatergic hippocampal terminals (Talbot et al., 2004). Reduced mRNA expression in dorsolateral prefrontal cortex (Weickert et al., 2004).

Irish studyMorris et al, 2007

ENTH Epsin 4 OMIM 607262 GeneCards

Transport of synaptic vesicles (Pimm et al., 2005)

5q33.3  SCZD1 MIM 181510

Associated with schizophrenia in a British study (Pimm et al., 2005) and in a chinese family study (Tang et al 2006) PUBMED

SNAP29 OMIM 604202 GeneCards

Syntaxin binding protein involved in glutamate release; Binds to STX1A

22q11.21 MIM 181500

Association reported in an American case study (Saito et al., 2001) PUBMED

SYN2 Synapsin II OMIM 600755 GeneCards

Associated with synaptic vesicles and glutamate release. Binds to CAPON and SYN3 .Expression regulated by DRD1 and DRD2 receptors (Chong et al, 2006)

3p25 MIM 181500

Association in Chinese and Korean case studies (Chen et al., 2004a;Lee et al., 2005) and in a family based chinese study {8923} PUBMED

Reduced frontal cortex (Mirnics et al., 2000)and hippocampal mRNA(Vawter et al., 2002b)

SYN3 Synapsin III OMIM 602705 GeneCards

Associated with synaptic vesicles and glutamate release. Binds to CAPON and SYN2

22q12.3 MIM 181500

Association reported in American case studies(Lachman et al., 2005;Porton et al., 2004) PUBMED

STX1A Syntaxin 1a OMIM 186590 GeneCards

Function in vesicle fusion and transmitter release
Binds to complexins, SLC6A3, SLC6A4, and SNAP29

7q11.23. 7q11 described as a putative locus in an American study(Blouin et al., 1998)

Association reported in a Canadian case study (Wong et al., 2004). PUBMED

Increased protein expression in cingulate cortex, increased mRNA in temporal cortex (Gabriel et al., 1997;Sokolov et al., 2000)

SYNGR1 Synaptogyrin 1 OMIM 603925 GeneCards

Associated with presynaptic vesicles.

22q13.1 MIM 181500

Nonsense mutation in an Indian family (Verma et al., 2004). Association also revealed in non-familial cases (Verma et al., 2005a) PUBMED

GABBR1 GABA-B receptor 1

OMIM 603540 GeneCards

Agonists inhibit glutamate release.Binds to ATF4 and ATF5 White at al, 2000(as does DISC1).
Also associates with YWHAH (Couve at al, 2001)

6p21.31 Cited in Genome scan meta-analysisLewis et al., 2003)

Weakly associated with schizophrenia in Japanese family and European case studies (Imai et al., 2002) (Zai et al., 2005). PUBMED

Reduced protein in temporal and entorhinal cortex and hippocampus (Mizukami et al., 2000;Mizukami et al., 2002)

GRM3 Metabotropic glutamate receptor mgluR3 OMIM 601115 GeneCards

Binds to PICK1 . Agonists inhibit glutamate release.

7q21.1-q21.2: 7q21 is also a translocation breakpoint in familial childhood schizophrenia (Yan et al., 2000)

Association reported in Japanese and Chinese case studies (Fujii et al., 2003) (Chen et al., 2005) and in a family based American  study (Egan et al., 2004) PUBMED

Increased prefrontal expression of mGluR1a and mGluR2/3 immunoreactivity in schizophrenia, (Gupta et al., 2005) No change in frontal cortex (Crook et al., 2002). Prefrontal N-acetylaspartate levels are lower in patients homozygous for the SNP polymorphism associated with schizophrenia and mRNA levels of the glutamate transporter SLC1A2 reduced post-mortem (Egan et al., 2004).

GRM4 Metabotropic glutamate receptor mgluR4  OMIM 604100 GeneCards

Agonists inhibit glutamate release

6p21.3.  Cited in Genome scan meta-analysis (Lewis et al., 2003)

Association reported in Ashenazi Jewish families (Fallin et al., 2005) PUBMED

No changes in protein expression in prefrontal cortex (Gupta et al., 2005)

GRM8 Metabotropic glutamate receptor mgluR8 OMIM 601116 GeneCards

Agonists inhibit glutamate release

7q31.3-q32.1: Linkage with 7q31 mentioned in an American study(Detera-Wadleigh et al., 1999)

Associated with schizophrenia in a Japanese case study (Takaki et al., 2004) PUBMED

No change in thalamic expression (Richardson-Burns et al., 2000)

Other genes whose products affect glutamate release or uptake

BDNF enhances depolarization-evoked glutamate release in cortical neurones (Balkowiec and Katz, 2002). Nicotinic CHRNA7 agonists stimulate glutamate release in the hippocampus and frontal cortex (Liu et al., 2003b;Marchi et al., 2002).CNR1 agonists inhibit glutamate  release in a number of brain regions (Wang, 2003) (Gerdeman and Lovinger, 2001). GRM3, GRM4 and GRM8 receptor activation inhibits glutamate release (DD and Marek, 2002;Guo and Ikeda, 2005). HTR2A agonists stimulate frontal cortical glutamate release (Aghajanian and Marek, 1999), HTR6 receptor antagonism selectively increases glutamate release in the frontal cortex and hippocampus (Dawson et al., 2001). DRD2 receptor activation  inhibits striatal and accumbens glutamate release (Bamford et al, 2004, Kalivas and Duffy, 1997))  HTR7 stimulation inhibits glutamate release in the dorsal raphe (Harsing, Jr. et al., 2004). IL1B and TNFA inhibit glutamate uptake into astrocytes and this effect is blocked by NO synthase inhibitors and mimicked by NO donors (Hu et al., 2000;Ye and Sontheimer, 1996). S100B stimulates glutamate uptake into astrocytes (Tramontina et al, 2006). NPY inhibits hippocampal glutamate release and blocks LTP(Whittaker et al., 1999).

Table 3: Genes coding for glutamate receptors and scaffold proteins, and related. Kegg pathays (Schizophrenia genes in red surround) Long-term potentiation Long-term depression

AMPA receptor

Binds to PICK1,GRIA4, HOMER1

GRIA4 (AMPA receptor subunit )
OMIM 138246 GeneCards

AMPA receptor: Binds to PICK1 (Xia et al., 1999) and GRIA1

11q22 MIM 181500

Association demonstrated in a Japanese case study(Makino et al., 2003). PUBMED

No expression change in Substantia nigra (Mueller et al., 2004), cortical and striatal regions (Healy et al., 1998) or thalamus (Ibrahim et al., 2000).Increased mRNA in the dorsolateral prefrontal and occipital cortex (Dracheva et al., 2005b)

GRIK3 Kainate receptor

OMIM 138243 GeneCards

Kainate receptor subunit

1p34.3 Cited in Genome scan meta-analysis(Lewis et al., 2003)

Association reported in an Italian case study (Begni et al., 2002).  PUBMED

Expression decreased in superior frontal gyrus of neuroleptic free but not neuroleptic treated schizophrenic patients (Sokolov, 1998). Relatively increased mRNA of GLUR7 at the expense of KA2 expression in the prefrontal cortex reported in schizophrenia and associated with decreases in kainate receptor binding (Meador-Woodruff et al., 2001). Reduction in immunoreactivity for glur5/6/7  in hippocampal dendrites  in CA1, CA2 and CA3 (Benes et al., 2001).

GRIK4 Kainate receptor

OMIM 600282 GeneCards

GRID1 glutamate receptor, ionotropic, delta 1 GeneCards

10q22 (MIM 181500, 2005)

Association reported in Askenazi Jewish families (Fallin et al., 2005) 
PUBMED

GRIN1 (NMDA receptor subunit NR1) OMIM 138249 GeneCards

Binds to GRIN2A, GRIN2B, DLG2

9q34.3 ; 9q34.3 is linked with schizophrenia in a South African population  (Riley et al., 1997). 9q32-9q34 shows evidence consistent with linkage in African American families (Kaufmann et al.., 1998)  

Association reported in American, Chinese and Italian case studies (Begni et al., 2003;Martucci et al., 2003;Qin et al., 2005; Zhao et al, 2006). PUBMED

Decreased phosphorylation in brain (Emamian et al., 2004b): Increased expression in substantia nigra (PC) (Mueller et al., 2004) and thalamus (Ibrahim et al., 2000): No change in frontal or temporal cortex (Akbarian et al., 1996). Increased expression of the unspliced NR1 variant in the superior temporal gyrus (Le Corre et al., 2000). Decreased hippocampal mRNA expression (Gao et al., 2000).

GRIN2A NMDA receptor subunit NR2A OMIM 138253 GeneCards

Binds to GRIN1, DLG2

16p13.2 MIM 181500

Association reported in two Japanese case studies (Itokawa et al., 2003b;Iwayama-Shigeno et al., 2005) PUBMED

No expression change in Substantia nigra (Mueller et al., 2004)or frontal or temporal cortex (Akbarian et al., 1996)

GRIN2B NMDA receptor subunit NR2B OMIM 138252 GeneCards

Binds to GRIN1, DLG2

12p12: D12S77 at 12p12 is linked with schizophrenia in a South African population  (Riley et al., 1997).

Association reported in Japanese Chinese and Italian case studies. (Di Maria et al., 2004;Miyatake et al., 2002;Ohtsuki et al., 2001)) PUBMED

Increased thalamic (Clinton et al., 2003;Ibrahim et al., 2000) and hippocampal  (Gao et al., 2000) expression.  No expression change in Substantia nigra (Mueller et al., 2004): Increased ifenprodil binding in superior temporal but not premotor cortex (Grimwood et al., 1999;Ibrahim et al., 2000);No expression change in frontal or temporal cortex (Akbarian et al., 1996)

GRIN2D NMDA receptor subunit NR2D OMIM 602717 GeneCards

Binds to GRIN1

19q13.1-qter

Association reported in a Japanese case study (Makino et al., 2005) PUBMED

Increased mRNA expression in prefrontal cortex (Akbarian et al., 1996).

GRM5 Metabotropic glutamate receptor mgluR5 OMIM  604102 GeneCards

GRM5 receptor activation potentiates both AMPA and NMDA receptor mediated responses (Ugolini et al., 1999) (Awad et al., 2000;Doherty et al., 2000) Interacts with RGS4 Schwenst and McGinty, 2007

 11q14.3 (MIM 181500

Association in a British case study (Devon et al., 2001). Located at the Chromosome 11 breakpoint associated with schizophrenia (Semple et al., 2001) . PUBMED

Increased expression in prefrontal cortex (Ohnuma et al., 1998b); Unmodified in hippocampus (Ohnuma et al., 2000)

Binds to PSD-95 and GRIN2B and is a component of the NMDA receptor  PSD-95 complex  (Yanai et al, 2000)

ARVCF armadillo repeat gene deleted in velocardiofacial syndrome OMIM 602269 GeneCards

ARVCF binds to the PDZ domain of erbin (ERBB2IP) (Laura et al., 2002) a protein concentrated in postsynaptic membranes which binds to PSD-95 and to the NRG1 receptor ERBB2 (Huang et al., 2001)

22q11.21 MIM 181500

Possible association in a Chinese family study (Xie et al., 2005). PUBMED

ATXN1 (SCA1): ataxin 1) OMIM 601556 GeneCards

Metabotropic mGluR1 (GRM1), NMDA-like  (GRID1/GRID2) and AMPA receptor GRIA2/3 trafficking is altered in mutant ATXN1 transgenic mice (Skinner et al., 2001). Possible role in ubiquitin-proteasome and chaperone system Davidson et al, 2000  

6p23 MIM 181500

CAG repeats in this gene have been reported to associate with schizophrenia in American case (Joo et al., 1999)or family (Pujana et al., 1997)studies  (Pujana et al., 1997).Association also reported in Ashkenazi Jewish families (Fallin et al., 2005)

DLG2 Chapsyn-110 

OMIM 603583 GeneCards

Postsynaptic scaffold protein; Binds to GRIN1, GRIN2A, GRIN2B, NOS1 and NRG1 receptor ERBB4

11q21 MIM 181500

DLG2 polymorphisms have not been reported in schizophrenia. However, PSZA11q14 is located in the first intron of and is antisense to DLG2 and has been suggested as a candidate gene for schizophrenia (Polesskaya et al., 2003).PUBMED 

The expression of PSZA11q14 is reduced in the frontal cortex in schizophrenic patients (Polesskaya et al., 2003).

DRPLA dentatorubral-pallidoluysian atrophy or atrophin-1 OMIM 607462 GeneCards

Interacts with an insulin receptor tyrosine kinase substrate BAIAP2 (Okamura-Oho et al., 1999) which is localised in postsynaptic densities and binds to PSD-95 and DLG2 (Choi et al., 2005).

12p13.31

Possible association of a CAG repeat in one family study(Morris-Rosendahl et al., 1997). PUBMED

HOMER1 OMIM 604798 GeneCards

Controls the localisation and clustering of Group 1 metabotropic glutamate receptors, GRM1 and GRM5 (Ango et al., 2000;Tadokoro et al., 1999). NMDA and GRM5 receptors are linked via HOMER and Shank (Tu et al., 1999). Gene ID 9456

5q14.2 MIM 181500

Borderline association in a British case study (Norton et al., 2003). PUBMED

LGI1 leucine-rich