Abstract
The G72/G30 gene complex is a candidate gene for schizophrenia and bipolar disorder. However, G72 and G30 mRNAs are expressed at very low levels in human brain, with only rare splicing forms observed. We report here G72/G30 expression profiles and behavioral changes in a G72/G30 transgenic mouse model. A human BAC clone containing the G72/G30 genomic region was used to establish the transgenic mouse model, on which gene expression studies, western blot and behavioral tests were performed. Relative to their minimal expression in humans, G72 and G30 mRNAs were highly expressed in the transgenic mice, and had a more complex splicing pattern. The highest G72 transcript levels were found in testis, followed by cerebral cortex, with very low or undetectable levels in other tissues. No LG72 (the long putative isoform of G72) protein was detected in the transgenic mice. Whole-genome expression profiling identified 361 genes differentially expressed in transgenic mice compared with wild-type, including genes previously implicated in neurological and psychological disorders. Relative to wild-type mice, the transgenic mice exhibited fewer stereotypic movements in the open field test, higher baseline startle responses in the course of the prepulse inhibition test, and lower hedonic responses in the sucrose preference test. The transcriptome profile changes and multiple mouse behavioral effects suggest that the G72 gene may play a role in modulating behaviors relevant to psychiatric disorders.
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References
Blouin JL, Dombroski BA, Nath SK, Lasseter VK, Wolyniec PS, Nestadt G et al. Schizophrenia susceptibility loci on chromosomes 13q32 and 8p21. Nat Genet 1998; 20: 70–73.
Levinson DF, Holmans P, Straub RE, Owen MJ, Wildenauer DB, Gejman PV et al. Multicenter linkage study of schizophrenia candidate regions on chromosomes 5q, 6q, 10p, and 13q: schizophrenia linkage collaborative group III. Am J Hum Genet 2000; 67: 652–663.
Liu C, Badner JA, Christian SL, Guroff JJ, tera-Wadleigh SD, Gershon ES . Fine mapping supports previous linkage evidence for a bipolar disorder susceptibility locus on 13q32. Am J Med Genet 2001; 105: 375–380.
Badner JA, Gershon ES . Meta-analysis of whole-genome linkage scans of bipolar disorder and schizophrenia. Mol Psychiatry 2002; 7: 405–411.
Chumakov I, Blumenfeld M, Guerassimenko O, Cavarec L, Palicio M, Abderrahim H et al. Genetic and physiological data implicating the new human gene G72 and the gene for D-amino acid oxidase in schizophrenia. Proc Natl Acad Sci USA 2002; 99: 13675–13680.
Mulle JG, Chowdari KV, Nimgaonkar V, Chakravarti A . No evidence for association to the G72/G30 locus in an independent sample of schizophrenia families. Mol Psychiatry 2005; 10: 431–433.
Liu YL, Fann CS, Liu CM, Chang CC, Wu JY, Hung SI et al. No association of G72 and D-amino acid oxidase genes with schizophrenia. Schizophr Res 2006; 87: 15–20.
Wood LS, Pickering EH, Dechairo BM . Significant support for DAO as a schizophrenia susceptibility locus: examination of five genes putatively associated with schizophrenia. Biol Psychiatry 2007; 61: 1195–1199.
Vilella E, Costas J, Sanjuan J, Guitart M, De DY, Carracedo A et al. Association of schizophrenia with DTNBP1 but not with DAO, DAOA, NRG1 and RGS4 nor their genetic interaction. J Psychiatr Res 2008; 42: 278–288.
Shi J, Badner JA, Gershon ES, Chunyu L, Willour VL, Potash JB . Further evidence for an association of G72/G30 with schizophrenia in Chinese. Schizophr Res 2009; 107: 324–326.
Maier W, Hofgen B, Zobel A, Rietschel M . Genetic models of schizophrenia and bipolar disorder: overlapping inheritance or discrete genotypes? Eur Arch Psychiatry Clin Neurosci 2005; 255: 159–166.
McGuffin P, Tandon K, Corsico A . Linkage and association studies of schizophrenia. Curr Psychiatry Rep 2003; 5: 121–127.
Craddock N, Forty L . Genetics of affective (mood) disorders. Eur J Hum Genet 2006; 14: 660–668.
DePaulo JR . Genetics of bipolar disorder: where do we stand? Am J Psychiatry 2004; 161: 595–597.
Craddock N, O'Donovan MC, Owen MJ . The genetics of schizophrenia and bipolar disorder: dissecting psychosis. J Med Genet 2005; 42: 193–204.
Craddock N, O′Donovan MC, Owen MJ . Genes for schizophrenia and bipolar disorder? Implications for psychiatric nosology. Schizophr Bull 2006; 32: 9–16.
Bass NJ, Datta SR, McQuillin A, Puri V, Choudhury K, Thirumalai S et al. Evidence for the association of the DAOA (G72) gene with schizophrenia and bipolar disorder but not for the association of the DAO gene with schizophrenia. Behav Brain Funct 2009; 5: 28.
Muller DJ, Zai CC, Shinkai T, Strauss J, Kennedy JL . Association between the DAOA/G72 gene and bipolar disorder and meta-analyses in bipolar disorder and schizophrenia. Bipolar Disord 2011; 13: 198–207.
Krug A, Markov V, Krach S, Jansen A, Zerres K, Eggermann T et al. Genetic variation in G72 correlates with brain activation in the right middle temporal gyrus in a verbal fluency task in healthy individuals. Hum Brain Mapp 2011; 32: 118–126.
Prata DP, Papagni SA, Mechelli A, Fu CH, Kambeitz J, Picchioni M et al. Effect of D-amino acid oxidase activator (DAOA; G72) on brain function during verbal fluency. Hum Brain Mapp 2012; 33: 143–153.
Zuliani R, Moorhead TW, Job D, McKirdy J, Sussmann JE, Johnstone EC et al. Genetic variation in the G72 (DAOA) gene affects temporal lobe and amygdala structure in subjects affected by bipolar disorder. Bipolar Disord 2009; 11: 621–627.
Hattori E, Liu C, Badner JA, Bonner TI, Christian SL, Maheshwari M et al. Polymorphisms at the G72/G30 gene locus, on 13q33, are associated with bipolar disorder in two independent pedigree series. Am J Hum Genet 2003; 72: 1131–1140.
Konradi C, Heckers S . Molecular aspects of glutamate dysregulation: implications for schizophrenia and its treatment. Pharmacol Ther 2003; 97: 153–179.
Sacchi S, Bernasconi M, Martineau M, Mothet JP, Ruzzene M, Pilone MS et al. pLG72 modulates intracellular D-serine levels through its interaction with D-amino acid oxidase: effect on schizophrenia susceptibility. J Biol Chem 2008; 283: 22244–22256.
Kvajo M, Dhilla A, Swor DE, Karayiorgou M, Gogos JA . Evidence implicating the candidate schizophrenia/bipolar disorder susceptibility gene G72 in mitochondrial function. Mol Psychiatry 2008; 13: 685–696.
Otte DM, Bilkei-Gorzo A, Filiou MD, Turck CW, Yilmaz O, Holst MI et al. Behavioral changes in G72/G30 transgenic mice. Eur Neuropsychopharmacol 2009; 19: 339–348.
Otte DM, Sommersberg B, Kudin A, Guerrero C, Albayram O, Filiou MD et al. N-acetyl cysteine treatment rescues cognitive deficits induced by mitochondrial dysfunction in G72/G30 transgenic mice. Neuropsychopharmacology 2011; 36: 2233–2243.
Johnson WE, Li C, Rabinovic A . Adjusting batch effects in microarray expression data using empirical Bayes methods. Biostatistics 2007; 8: 118–127.
Modrek B, Lee CJ . Alternative splicing in the human, mouse and rat genomes is associated with an increased frequency of exon creation and/or loss. Nat Genet 2003; 34: 177–180.
Xing Y, Lee C . Alternative splicing and RNA selection pressure—evolutionary consequences for eukaryotic genomes. Nat Rev Genet 2006; 7: 499–509.
Cheng MC, Lu CL, Luu SU, Tsai HM, Hsu SH, Chen TT et al. Genetic and functional analysis of the DLG4 gene encoding the post-synaptic density protein 95 in schizophrenia. PLoS One 2010; 5: e15107.
Bray NJ, Kirov G, Owen RJ, Jacobsen NJ, Georgieva L, Williams HJ et al. Screening the human protocadherin 8 (PCDH8) gene in schizophrenia. Genes Brain Behav 2002; 1: 187–191.
Jungerius BJ, Hoogendoorn ML, Bakker SC, Van′t SR, Bardoel AF, Ophoff RA et al. An association screen of myelin-related genes implicates the chromosome 22q11 PIK4CA gene in schizophrenia. Mol Psychiatry 2008; 13: 1060–1068.
Ye L, Sun Z, Xie L, Liu S, Ju G, Shi J et al. Further study of a genetic association between the CLDN5 locus and schizophrenia. Schizophr Res 2005; 75: 139–141.
Wu N, Zhang X, Jin S, Liu S, Ju G, Wang Z et al. A weak association of the CLDN5 locus with schizophrenia in Chinese case-control samples. Psychiatry Res 2010; 178: 223.
Hong LE, Wonodi I, Avila MT, Buchanan RW, McMahon RP, Mitchell BD et al. Dihydropyrimidinase-related protein 2 (DRP-2) gene and association to deficit and nondeficit schizophrenia. Am J Med Genet B Neuropsychiatr Genet 2005; 136B: 8–11.
Ohtsuki T, Sakurai K, Dou H, Toru M, Yamakawa-Kobayashi K, Arinami T . Mutation analysis of the NMDAR2B (GRIN2B) gene in schizophrenia. Mol Psychiatry 2001; 6: 211–216.
Fallin MD, Lasseter VK, Avramopoulos D, Nicodemus KK, Wolyniec PS, McGrath JA et al. Bipolar I disorder and schizophrenia: a 440-single-nucleotide polymorphism screen of 64 candidate genes among Ashkenazi Jewish case-parent trios. Am J Hum Genet 2005; 77: 918–936.
Lerer B, Macciardi F, Segman RH, Adolfsson R, Blackwood D, Blairy S et al. Variability of 5-HT2C receptor cys23ser polymorphism among European populations and vulnerability to affective disorder. Mol Psychiatry 2001; 6: 579–585.
Segman RH, Heresco-Levy U, Finkel B, Inbar R, Neeman T, Schlafman M et al. Association between the serotonin 2C receptor gene and tardive dyskinesia in chronic schizophrenia: additive contribution of 5-HT2Cser and DRD3gly alleles to susceptibility. Psychopharmacology (Berl) 2000; 152: 408–413.
Goldstein I, Lerer E, Laiba E, Mallet J, Mujaheed M, Laurent C et al. Association between sodium- and potassium-activated adenosine triphosphatase alpha isoforms and bipolar disorders. Biol Psychiatry 2009; 65: 985–991.
Lee KY, Ahn YM, Joo EJ, Chang JS, Kim YS . The association of DUSP6 gene with schizophrenia and bipolar disorder: its possible role in the development of bipolar disorder. Mol Psychiatry 2006; 11: 425–426.
Borsotto M, Cavarec L, Bouillot M, Romey G, Macciardi F, Delaye A et al. PP2A-Bgamma subunit and KCNQ2 K+ channels in bipolar disorder. Pharmacogenomics J 2007; 7: 123–132.
Benzel I, Kew JN, Viknaraja R, Kelly F, de BJ, Hirsch S et al. Investigation of G72 (DAOA) expression in the human brain. BMC Psychiatry 2008; 8: 94.
Ridley RM . The psychology of perserverative and stereotyped behaviour. Prog Neurobiol 1994; 44: 221–231.
Garner JP, Meehan CL, Mench JA . Stereotypies in caged parrots, schizophrenia and autism: evidence for a common mechanism. Behav Brain Res 2003; 145: 125–134.
Morrens M, Hulstijn W, Lewi PJ, De HM, Sabbe BG . Stereotypy in schizophrenia. Schizophr Res 2006; 84: 397–404.
Kennes D, Odberg FO, Bouquet Y, De Rycke PH . Changes in naloxone and haloperidol effects during the development of captivity-induced jumping stereotypy in bank voles. Eur J Pharmacol 1988; 153: 19–24.
Garner JP, Mason GJ . Evidence for a relationship between cage stereotypies and behavioural disinhibition in laboratory rodents. Behav Brain Res 2002; 136: 83–92.
Andreasen NC, Olsen S . Negative v positive schizophrenia. Definition and validation. Arch Gen Psychiatry 1982; 39: 789–794.
Feyder M, Karlsson RM, Mathur P, Lyman M, Bock R, Momenan R et al. Association of mouse Dlg4 (PSD-95) gene deletion and human DLG4 gene variation with phenotypes relevant to autism spectrum disorders and Williams' syndrome. Am J Psychiatry 2010; 167: 1508–1517.
Feng W, Zhang M . Organization and dynamics of PDZ-domain-related supramodules in the postsynaptic density. Nat Rev Neurosci 2009; 10: 87–99.
Ohnuma T, Kato H, Arai H, Faull RL, McKenna PJ, Emson PC . Gene expression of PSD95 in prefrontal cortex and hippocampus in schizophrenia. Neuroreport 2000; 11: 3133–3137.
Tam GW, van de Lagemaat LN, Redon R, Strathdee KE, Croning MD, Malloy MP et al. Confirmed rare copy number variants implicate novel genes in schizophrenia. Biochem Soc Trans 2010; 38: 445–451.
Vetter DE, Mann JR, Wangemann P, Liu J, McLaughlin KJ, Lesage F et al. Inner ear defects induced by null mutation of the isk gene. Neuron 1996; 17: 1251–1264.
Vidal PP, Degallaix L, Josset P, Gasc JP, Cullen KE . Postural and locomotor control in normal and vestibularly deficient mice. J Physiol 2004; 559 (Pt 2): 625–638.
Acknowledgements
This work was supported by 1R21MH083521, 4R33MH083521 (to CL) and the Geraldi Norton Foundation and the Eklund Family. We are grateful to Dr Mirna Kvajo and Dr Joseph A Gogos at Columbia University, and Dr Guang Chen and Dr Husseini K Manji at NIMH for anti-G72 antibodies. We thank Dr Cristianne RM Frazier, Dr Jeff A Beeler and Dr Xiaoxi Zhuang at The University of Chicago for technical assistance and data analysis of the mouse sucrose preference test.
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The authors declared no biomedical financial interests or conflict of interest. The views expressed in this manuscript are not necessarily those of NIH. The sequences of 13 novel G72 splicing forms identified in human and transgenic mouse model have been accepted by NCBI GenBank (www.ncbi.nlm.nih.gov/genbank), with accession numbers as indicated in Figure 1b.
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Cheng, L., Hattori, E., Nakajima, A. et al. Expression of the G72/G30 gene in transgenic mice induces behavioral changes. Mol Psychiatry 19, 175–183 (2014). https://doi.org/10.1038/mp.2012.185
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DOI: https://doi.org/10.1038/mp.2012.185
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