Abstract
The dysbindin-1 and neuregulin-1 (NRG-1) genes are related to schizophrenia. Expression studies in postmortem brains have revealed lower expression of dysbindin-1 and higher expression of NRG-1 in brain tissue from subjects with schizophrenia. In addition to the difficulty of sampling, the use of postmortem brain tissues is not ideal because these tissues are heterogeneous with respect to biochemical parameters, lifetime history of medications and physiological status at the time of death. In contrast, medication and environmental influences that could mask the genetic basis of differences in RNA expression are removed in immortalized lymphocytes by culturing. Only a few microarray analysis studies using immortalized lymphocytes in schizophrenia have been reported, and whether immortalized lymphocytes are an appropriate alternative to neuronal tissue remains controversial. In this study, we measured the mRNA expression levels of dysbindin-1, NRG-1 and two other genes (NPY1R and GNAO1) in immortalized lymphocytes from 45 patients with schizophrenia and 45 controls using real-time quantitative reverse transcriptase-PCR. No difference was observed between patients and controls with respect to the expression of dysbindin-1, NRG-1, NPY1R or GNAO1 gene. Our findings suggest that the gene expression profile of immortalized lymphocyte from schizophrenic patients is different from that in postmortem brain tissue at least with respect to the dysbindin-1 and NRG-1 genes.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Gill, M., Donohoe, G. & Corvin, A. What have the genomics ever done for the psychoses? Psychol. Med. 40, 529–540 (2010).
Hashimoto, R., Noguchi, H., Hori, H., Ohi, K., Yasuda, Y., Takeda, M. et al. Association between the dysbindin gene (DTNBP1) and cognitive functions in Japanese subjects. Psychiatry Clin. Neurosci. 63, 550–556 (2009).
Hashimoto, R., Noguchi, H., Hori, H., Nakabayashi, T., Suzuki, T., Iwata, N. et al. A genetic variation in the dysbindin gene (DTNBP1) is associated with memory performance in healthy controls. World J. Biol. Psychiatry 11, 431–438 (2010).
Burdick, K. E., Lencz, T., Funke, B., Finn, C. T., Szeszko, P. R., Kane, J. M. et al. Genetic variation in DTNBP1 influences general cognitive ability. Hum. Mol. Genet. 15, 1563–1568 (2006).
Murotani, T., Ishizuka, T., Hattori, S., Hashimoto, R., Matsuzaki, S. & Yamatodani, A. High dopamine turnover in the brains of Sandy mice. Neurosci. Lett. 421, 47–51 (2007).
Hattori, S., Murotani, T., Matsuzaki, S., Ishizuka, T., Kumamoto, N., Takeda, M. et al. Behavioral abnormalities and dopamine reductions in sdy mutant mice with a deletion in Dtnbp1, a susceptibility gene for schizophrenia. Biochem. Biophys. Res. Commun. 373, 298–302 (2008).
Takao, K., Toyama, K., Nakanishi, K., Hattori, S., Takamura, H., Takeda, M. et al. Impaired long-term memory retention and working memory in sdy mutant mice with a deletion in Dtnbp1, a susceptibility gene for schizophrenia. Mol. Brain 1, 11 (2008).
McIntosh, A. M., Moorhead, T. W., Job, D., Lymer, G. K., Munoz Maniega, S., McKirdy, J. et al. The effects of a neuregulin 1 variant on white matter density and integrity. Mol. Psychiatry 13, 1054–1059 (2008).
Stefansson, H., Sigurdsson, E., Steinthorsdottir, V., Bjornsdottir, S., Sigmundsson, T., Ghosh, S. et al. Neuregulin 1 and susceptibility to schizophrenia. Am. J. Hum. Genet. 71, 877–892 (2002).
Falls, D. L. Neuregulins and the neuromuscular system: 10 years of answers and questions. J. Neurocytol. 32, 619–647 (2003).
Steinthorsdottir, V., Stefansson, H., Ghosh, S., Birgisdottir, B., Bjornsdottir, S., Fasquel, A. C. et al. Multiple novel transcription initiation sites for NRG1. Gene 342, 97–105 (2004).
Hashimoto, R., Straub, R. E., Weickert, C. S., Hyde, T. M., Kleinman, J. E. & Weinberger, D. R. Expression analysis of neuregulin-1 in the dorsolateral prefrontal cortex in schizophrenia. Mol. Psychiatry 9, 299–307 (2004).
Deakin, I. H., Law, A. J., Oliver, P. L., Schwab, M. H., Nave, K. A., Harrison, P. J. et al. Behavioural characterization of neuregulin 1 type I overexpressing transgenic mice. Neuroreport 20, 1523–1528 (2009).
Talbot, K., Eidem, W. L., Tinsley, C. L., Benson, M. A., Thompson, E. W., Smith, R. J. et al. Dysbindin-1 is reduced in intrinsic, glutamatergic terminals of the hippocampal formation in schizophrenia. J. Clin. Invest. 113, 1353–1363 (2004).
Weickert, C. S., Straub, R. E., McClintock, B. W., Matsumoto, M., Hashimoto, R., Hyde, T. M. et al. Human dysbindin (DTNBP1) gene expression in normal brain and in schizophrenic prefrontal cortex and midbrain. Arch. Gen. Psychiatry 61, 544–555 (2004).
Law, A. J., Lipska, B. K., Weickert, C. S., Hyde, T. M., Straub, R. E., Hashimoto, R. et al. Neuregulin 1 transcripts are differentially expressed in schizophrenia and regulated by 5′ SNPs associated with the disease. Proc. Natl Acad. Sci. USA 103, 6747–6752 (2006).
Vawter, M. P., Barrett, T., Cheadle, C., Sokolov, B. P., Wood, W. H. III, Donovan, D. M. et al. Application of cDNA microarrays to examine gene expression differences in schizophrenia. Brain Res. Bull. 55, 641–650 (2001).
Chung, C., Tallerico, T. & Seeman, P. Schizophrenia hippocampus has elevated expression of chondrex glycoprotein gene. Synapse 50, 29–34 (2003).
Hakak, Y., Walker, J. R., Li, C., Wong, W. H., Davis, K. L., Buxbaum, J. D. et al. Genome-wide expression analysis reveals dysregulation of myelination-related genes in chronic schizophrenia. Proc. Natl Acad. Sci. USA 98, 4746–4751 (2001).
Tkachev, D., Mimmack, M. L., Ryan, M. M., Wayland, M., Freeman, T., Jones, P. B. et al. Oligodendrocyte dysfunction in schizophrenia and bipolar disorder. Lancet 362, 798–805 (2003).
Sullivan, P. F., Fan, C. & Perou, C. M. Evaluating the comparability of gene expression in blood and brain. Am. J. Med. Genet. B Neuropsychiatr. Genet. 141B, 261–268 (2006).
Hranilovic, D., Stefulj, J., Schwab, S., Borrmann-Hassenbach, M., Albus, M., Jernej, B. et al. Serotonin transporter promoter and intron 2 polymorphisms: relationship between allelic variants and gene expression. Biol. Psychiatry 55, 1090–1094 (2004).
Maeda, K., Nwulia, E., Chang, J., Balkissoon, R., Ishizuka, K., Chen, H. et al. Differential expression of disrupted-in-schizophrenia (DISC1) in bipolar disorder. Biol. Psychiatry 60, 929–935 (2006).
Sun, X., Young, L. T., Wang, J. F., Grof, P., Turecki, G., Rouleau, G. A. et al. Identification of lithium-regulated genes in cultured lymphoblasts of lithium responsive subjects with bipolar disorder. Neuropsychopharmacology 29, 799–804 (2004).
Vawter, M. P., Ferran, E., Galke, B., Cooper, K., Bunney, W. E. & Byerley, W. Microarray screening of lymphocyte gene expression differences in a multiplex schizophrenia pedigree. Schizophr. Res. 67, 41–52 (2004).
Liu, Y. L., Fann, C. S., Liu, C. M., Chang, C. C., Yang, W. C., Hung, S. I. et al. More evidence supports the association of PPP3CC with schizophrenia. Mol. Psychiatry 12, 966–974 (2007).
Matigian, N. A., McCurdy, R. D., Feron, F., Perry, C., Smith, H., Filippich, C. et al. Fibroblast and lymphoblast gene expression profiles in schizophrenia: are non-neural cells informative? PLoS One 3, e2412 (2008).
Chagnon, Y. C., Roy, M. A., Bureau, A., Merette, C. & Maziade, M. Differential RNA expression between schizophrenic patients and controls of the dystrobrevin binding protein 1 and neuregulin 1 genes in immortalized lymphocytes. Schizophr. Res. 100, 281–290 (2008).
Numakawa, T., Yagasaki, Y., Ishimoto, T., Okada, T., Suzuki, T., Iwata, N. et al. Evidence of novel neuronal functions of dysbindin, a susceptibility gene for schizophrenia. Hum. Mol. Genet. 13, 2699–2708 (2004).
Hikita, T., Taya, S., Fujino, Y., Taneichi-Kuroda, S., Ohta, K., Tsuboi, D. et al. Proteomic analysis reveals novel binding partners of dysbindin, a schizophrenia-related protein. J. Neurochem. 110, 1567–1574 (2009).
Hahn, C. G., Wang, H. Y., Cho, D. S., Talbot, K., Gur, R. E., Berrettini, W. H. et al. Altered neuregulin 1-erbB4 signaling contributes to NMDA receptor hypofunction in schizophrenia. Nat. Med. 12, 824–828 (2006).
Sei, Y., Ren-Patterson, R., Li, Z., Tunbridge, E. M., Egan, M. F., Kolachana, B. S. et al. Neuregulin1-induced cell migration is impaired in schizophrenia: association with neuregulin1 and catechol-o-methyltransferase gene polymorphisms. Mol. Psychiatry 12, 946–957 (2007).
Acknowledgements
We thank all the individuals who participated in this study. This work was funded in part by Grants-in-Aid from the Japanese Ministry of Health, Labor and Welfare (H19-kokoro-002); the Japanese Ministry of Education, Culture, Sports, Science and Technology (18689030); CREST of JST; and the Japan Foundation for Neuroscience and Mental Health and by a Grant-aid for Scientific Research on Priority Areas -Research on Pathomechanisms of Brain Disorders- from the MEXT (18023045). Postmortem brains were kindly donated by the Stanley Foundation.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Yamamori, H., Hashimoto, R., Verrall, L. et al. Dysbindin-1 and NRG-1 gene expression in immortalized lymphocytes from patients with schizophrenia. J Hum Genet 56, 478–483 (2011). https://doi.org/10.1038/jhg.2011.40
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/jhg.2011.40
Keywords
This article is cited by
-
Antipsychotic drugs increase Neuregulin1β1 serum levels in first-episode drug-naïve patients and chronic schizophrenia with suggestions for improving the treatment of psychotic symptoms
BMC Psychiatry (2022)
-
Altered gene expression in lymphoblastoid cell lines after subculture
In Vitro Cellular & Developmental Biology - Animal (2018)
-
Elevated peripheral expression of neuregulin-1 (NRG1) mRNA isoforms in clozapine-treated schizophrenia patients
Translational Psychiatry (2017)
-
Emerging roles of ARHGAP33 in intracellular trafficking of TrkB and pathophysiology of neuropsychiatric disorders
Nature Communications (2016)
-
Increased dysbindin-1B isoform expression in schizophrenia and its propensity in aggresome formation
Cell Discovery (2015)


