Skip Navigation


Human Molecular Genetics Advance Access originally published online on September 2, 2004
Human Molecular Genetics 2004 13(21):2699-2708; doi:10.1093/hmg/ddh280
This Article
Right arrow Full Text Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
13/21/2699    most recent
ddh280v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (123)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Numakawa, T.
Right arrow Articles by Hashimoto, R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Numakawa, T.
Right arrow Articles by Hashimoto, R.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Human Molecular Genetics, Vol. 13, No. 21 © Oxford University Press 2004; all rights reserved

Evidence of novel neuronal functions of dysbindin, a susceptibility gene for schizophrenia

Tadahiro Numakawa1, Yuki Yagasaki1, Tetsuya Ishimoto2, Takeya Okada1, Tatsuyo Suzuki3, Nakao Iwata3, Norio Ozaki4, Takahisa Taguchi2, Masahiko Tatsumi5, Kunitoshi Kamijima5, Richard E. Straub6, Daniel R. Weinberger6, Hiroshi Kunugi1 and Ryota Hashimoto1,*

1Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashicho, Kodaira, Tokyo 187-8502, Japan, 2Neuronics R.G. Special Division for Human Life Technology, National Institute of Advanced Industrial Science and Technology, 1-8-31 Midorigaoka, Ikeda, Osaka 563-8577, Japan, 3Department of Psychiatry, Fujita Health University School of Medicine, 1-98 Kutsukakechotagakugakubo, Toyoake, Aichi 470-1192, Japan, 4Department of Psychiatry, Nagoya University Graduate School of Medicine, 65 Tsurumai, Chuoku, Nagoya, Aichi 466-8550, Japan, 5Department of Psychiatry, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawaku, Tokyo 142-8666, Japan and 6Clinical Brain Disorders Branch, National Institute of Mental Health, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892, USA

Received May 13, 2004; Accepted August 23, 2004

Genetic variation in dysbindin (DTNBP1: dystrobrevin-binding protein 1) has recently been shown to be associated with schizophrenia. The dysbindin gene is located at chromosome 6p22.3, one of the most promising susceptibility loci in schizophrenia linkage studies. We attempted to replicate this association in a Japanese sample of 670 patients with schizophrenia and 588 controls. We found a nominally significant association with schizophrenia for four single nucleotide polymorphisms and stronger evidence for association in a multi-marker haplotype analysis (P=0.00028). We then explored functions of dysbindin protein in primary cortical neuronal culture. Overexpression of dysbindin induced the expression of two pre-synaptic proteins, SNAP25 and synapsin I, and increased extracellular basal glutamate levels and release of glutamate evoked by high potassium. Conversely, knockdown of endogenous dysbindin protein by small interfering RNA (siRNA) resulted in the reduction of pre-synaptic protein expression and glutamate release, suggesting that dysbindin might influence exocytotic glutamate release via upregulation of the molecules in pre-synaptic machinery. The overexpression of dysbindin increased phosphorylation of Akt protein and protected cortical neurons against neuronal death due to serum deprivation and these effects were blocked by LY294002, a phosphatidylinositol 3-kinase (PI3-kinase) inhibitor. SiRNA-mediated silencing of dysbindin protein diminished Akt phosphorylation and facilitated neuronal death induced by serum deprivation, suggesting that dysbindin promotes neuronal viability through PI3-kinase-Akt signaling. Genetic variants associated with impairments of these functions of dysbindin could play an important role in the pathogenesis of schizophrenia.

* To whom correspondence should be addressed. Tel: +81 423412711; Fax: +81 423461744; Email: rhashimo{at}ncnp.go.jp


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 ScienceHome page
D. K. Dickman and G. W. Davis
The Schizophrenia Susceptibility Gene dysbindin Controls Synaptic Homeostasis
Science, November 20, 2009; 326(5956): 1127 - 1130.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
Y. Ji, F. Yang, F. Papaleo, H.-X. Wang, W.-J. Gao, D. R. Weinberger, and B. Lu
Role of dysbindin in dopamine receptor trafficking and cortical GABA function
PNAS, November 17, 2009; 106(46): 19593 - 19598.
[Abstract] [Full Text] [PDF]

Home page
 JCBHome page
X.-W. Chen, Y.-Q. Feng, C.-J. Hao, X.-L. Guo, X. He, Z.-Y. Zhou, N. Guo, H.-P. Huang, W. Xiong, H. Zheng, et al.
DTNBP1, a schizophrenia susceptibility gene, affects kinetics of transmitter release
J. Cell Biol., October 20, 2008; 181(5): 791 - 801.
[Abstract] [Full Text] [PDF]

Home page
 Schizophr BullHome page
E. Ivleva, G. Thaker, and C. A. Tamminga
Comparing Genes and Phenomenology in the Major Psychoses: Schizophrenia and Bipolar 1 Disorder
Schizophr Bull, July 1, 2008; 34(4): 734 - 742.
[Full Text] [PDF]

Home page
 Schizophr BullHome page
N. J. Bray
Gene Expression in the Etiology of Schizophrenia
Schizophr Bull, May 1, 2008; 34(3): 412 - 418.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
Y. Iizuka, Y. Sei, D. R. Weinberger, and R. E. Straub
Evidence That the BLOC-1 Protein Dysbindin Modulates Dopamine D2 Receptor Internalization and Signaling But Not D1 Internalization
J. Neurosci., November 7, 2007; 27(45): 12390 - 12395.
[Abstract] [Full Text] [PDF]

Home page
 Br. J. PsychiatryHome page
J. M. McClellan, E. Susser, and M.-C. King
Schizophrenia: a common disease caused by multiple rare alleles
The British Journal of Psychiatry, March 1, 2007; 190(3): 194 - 199.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Biol. CellHome page
S. R. G. Setty, D. Tenza, S. T. Truschel, E. Chou, E. V. Sviderskaya, A. C. Theos, M. L. Lamoreux, S. M. Di Pietro, M. Starcevic, D. C. Bennett, et al.
BLOC-1 Is Required for Cargo-specific Sorting from Vacuolar Early Endosomes toward Lysosome-related Organelles
Mol. Biol. Cell, March 1, 2007; 18(3): 768 - 780.
[Abstract] [Full Text] [PDF]

Home page
 J. Cell Sci.Home page
K. Newell-Litwa, E. Seong, M. Burmeister, and V. Faundez
Neuronal and non-neuronal functions of the AP-3 sorting machinery
J. Cell Sci., February 15, 2007; 120(4): 531 - 541.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
R. Hashimoto, T. Numakawa, T. Ohnishi, E. Kumamaru, Y. Yagasaki, T. Ishimoto, T. Mori, K. Nemoto, N. Adachi, A. Izumi, et al.
Impact of the DISC1 Ser704Cys polymorphism on risk for major depression, brain morphology and ERK signaling
Hum. Mol. Genet., October 15, 2006; 15(20): 3024 - 3033.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
K. Talbot, D.-S. Cho, W.-Y. Ong, M. A. Benson, L.-Y. Han, H. A. Kazi, J. Kamins, C.-G. Hahn, D. J. Blake, and S. E. Arnold
Dysbindin-1 is a synaptic and microtubular protein that binds brain snapin
Hum. Mol. Genet., October 15, 2006; 15(20): 3041 - 3054.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Biol. CellHome page
G. Salazar, B. Craige, M. L. Styers, K. A. Newell-Litwa, M. M. Doucette, B. H. Wainer, J. M. Falcon-Perez, E. C. Dell'Angelica, A. A. Peden, E. Werner, et al.
BLOC-1 Complex Deficiency Alters the Targeting of Adaptor Protein Complex-3 Cargoes
Mol. Biol. Cell, September 1, 2006; 17(9): 4014 - 4026.
[Abstract] [Full Text] [PDF]

Home page
 FocusHome page
J. A. Gogos and D. J. Gerber
Schizophrenia Susceptibility Genes: Emergence of Positional Candidates and Future Directions
Focus, August 1, 2006; 4(3): 369.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
K. E. Burdick, T. Lencz, B. Funke, C. T. Finn, P. R. Szeszko, J. M. Kane, R. Kucherlapati, and A. K. Malhotra
Genetic variation in DTNBP1 influences general cognitive ability
Hum. Mol. Genet., May 15, 2006; 15(10): 1563 - 1568.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
Y. Yagasaki, T. Numakawa, E. Kumamaru, T. Hayashi, T.-P. Su, and H. Kunugi
Chronic Antidepressants Potentiate via Sigma-1 Receptors the Brain-derived Neurotrophic Factor-induced Signaling for Glutamate Release
J. Biol. Chem., May 5, 2006; 281(18): 12941 - 12949.
[Abstract] [Full Text] [PDF]

Home page
 J PsychopharmacolHome page
S. C. L. Gough and M. C. O'Donovan
Clustering of metabolic comorbidity in schizophrenia: a genetic contribution?
J Psychopharmacol, November 1, 2005; 19(6_suppl): 47 - 55.
[Abstract] [PDF]

Home page
 Am. J. PsychiatryHome page
K. S. KENDLER
Dr. Kendler Replies
Am J Psychiatry, October 1, 2005; 162(10): 1985 - 1986.
[Full Text] [PDF]

Home page
 Schizophr BullHome page
N. M Williams, M. C O'Donovan, and M. J Owen
Is the Dysbindin Gene (DTNBP1) a Susceptibility Gene for Schizophrenia?
Schizophr Bull, October 1, 2005; 31(4): 800 - 805.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
N. J. Bray, A. Preece, N. M. Williams, V. Moskvina, P. R. Buckland, M. J. Owen, and M. C. O'Donovan
Haplotypes at the dystrobrevin binding protein 1 (DTNBP1) gene locus mediate risk for schizophrenia through reduced DTNBP1 expression
Hum. Mol. Genet., July 15, 2005; 14(14): 1947 - 1954.
[Abstract] [Full Text] [PDF]

Home page
 J. Med. Genet.Home page
N Craddock, M C O'Donovan, and M J Owen
The genetics of schizophrenia and bipolar disorder: dissecting psychosis
J. Med. Genet., March 1, 2005; 42(3): 193 - 204.
[Abstract] [Full Text] [PDF]


Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.