Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

The dystrobrevin-binding protein 1 gene: features and networks

Abstract

The dystrobrevin-binding protein 1 (DTNBP1) gene has been one of the most studied and promising schizophrenia susceptibility genes since it was first reported to be associated with schizophrenia in the Irish Study of High Density Schizophrenia Families (ISHDSF). Although many studies have been performed both at the functional level and in association with psychiatric disorders, there has been no systematic review of the features of the DTNBP1 gene, protein or the relationship between function and phenotype. Using a bioinformatics approach, we identified the DTNBP1 gene in 13 vertebrate species. The comparison of these genes revealed a conserved gene structure, protein-coding sequence and dysbindin domain, but a diverse noncoding sequence. The molecular evolutionary analysis suggests the DTNBP1 gene probably originated in chordates and matured in vertebrates. No signature of recent positive selection was seen in any primate lineage. The DTNBP1 gene likely has many more alternative transcripts than the current three major isoforms annotated in the NCBI database. Our examination of risk haplotypes revealed that, although the frequency of a single nucleotide polymorphism (SNP) or haplotype might be significantly different in cases from controls, difference between major geographic populations was even larger. Finally, we constructed the first DTNBP1 interactome and explored its network features. Besides the biogenesis of lysosome-related organelles complex 1 and dystrophin-associated protein complex, several molecules in the DTNBP1 network likely provide insight into the role of DTNBP1 in biological systems: retinoic acid, β-estradiol, calmodulin and tumour necrosis factor. Studies of these subnetworks and pathways may provide opportunities to deepen our understanding of the mechanisms of action of DTNBP1 variants.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

References

  1. Benson MA, Newey SE, Martin-Rendon E, Hawkes R, Blake DJ . Dysbindin, a novel coiled-coil-containing protein that interacts with the dystrobrevins in muscle and brain. J Biol Chem 2001; 276: 24232–24241.

    CAS  Article  Google Scholar 

  2. Veroni C, Grasso M, Macchia G, Ramoni C, Ceccarini M, Petrucci TC et al. beta-dystrobrevin, a kinesin-binding receptor, interacts with the extracellular matrix components pancortins. J Neurosci Res 2007; 85: 2631–2639.

    CAS  Article  Google Scholar 

  3. Li W, Zhang Q, Oiso N, Novak EK, Gautam R, O’Brien EP et al. Hermansky–Pudlak syndrome type 7 (HPS-7) results from mutant dysbindin, a member of the biogenesis of lysosome-related organelles complex 1 (BLOC-1). Nat Genet 2003; 35: 84–89.

    CAS  Article  Google Scholar 

  4. Nazarian R, Starcevic M, Spencer MJ, Dell’Angelica EC . Reinvestigation of the dysbindin subunit of BLOC-1 (biogenesis of lysosome-related organelles complex-1) as a dystrobrevin-binding protein. Biochem J 2006; 395: 587–598.

    CAS  Article  Google Scholar 

  5. Starcevic M, Dell’Angelica EC . Identification of snapin and three novel proteins (BLOS1, BLOS2, and BLOS3/reduced pigmentation) as subunits of biogenesis of lysosome-related organelles complex-1 (BLOC-1). J Biol Chem 2004; 279: 28393–28401.

    CAS  Article  Google Scholar 

  6. Straub RE, Jiang Y, MacLean CJ, Ma Y, Webb BT, Myakishev MV et al. Genetic variation in the 6p22.3 gene DTNBP1, the human ortholog of the mouse dysbindin gene, is associated with schizophrenia. Am J Hum Genet 2002; 71: 337–348.

    CAS  Article  Google Scholar 

  7. van den Oord EJ, Sullivan PF, Jiang Y, Walsh D, O’Neill FA, Kendler KS et al. Identification of a high-risk haplotype for the dystrobrevin binding protein 1 (DTNBP1) gene in the Irish study of high-density schizophrenia families. Mol Psychiatry 2003; 8: 499–510.

    CAS  Article  Google Scholar 

  8. Allen NC, Bagade S, McQueen MB, Ioannidis JPA, Kavvoura FK, Khoury MJ et al. Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database. Nat Genet 2008; 40: 827–834.

    CAS  Article  Google Scholar 

  9. Li D, He L . Association study between the dystrobrevin binding protein 1 gene (DTNBP1) and schizophrenia: a meta-analysis. Schizophr Res 2007; 96: 112–118.

    Article  Google Scholar 

  10. Riley B, Kendler KS . Molecular genetic studies of schizophrenia. Eur J Hum Genet 2006; 14: 669–680.

    CAS  Article  Google Scholar 

  11. Sun J, Kuo P-H, Riley BP, Kendler KS, Zhao Z . Candidate genes for schizophrenia: a survey of association studies and gene ranking. Am J Med Genet B Neuropsychiatr Genet 2008; e-pub ahead of print.

  12. Breen G, Prata D, Osborne S, Munro J, Sinclair M, Li T et al. Association of the dysbindin gene with bipolar affective disorder. Am J Psychiatry 2006; 163: 1636–1638.

    Article  Google Scholar 

  13. Zinkstok JR, de Wilde O, van Amelsvoort TA, Tanck MW, Baas F, Linszen DH . Association between the DTNBP1 gene and intelligence: a case–control study in young patients with schizophrenia and related disorders and unaffected siblings. Behav Brain Funct 2007; 3: 19.

    Article  Google Scholar 

  14. O’Donovan MC, Williams NM, Owen MJ . Recent advances in the genetics of schizophrenia. Hum Mol Genet 2003; 12, Spec No 2 R125–R133.

    Article  Google Scholar 

  15. Owen MJ, Williams NM, O’Donovan MC . The molecular genetics of schizophrenia: new findings promise new insights. Mol Psychiatry 2004; 9: 14–27.

    CAS  Article  Google Scholar 

  16. Ross CA, Margolis RL, Reading SA, Pletnikov M, Coyle JT . Neurobiology of schizophrenia. Neuron 2006; 52: 139–153.

    CAS  Article  Google Scholar 

  17. Weickert CS, Straub RE, McClintock BW, Matsumoto M, Hashimoto R, Hyde TM et al. Human dysbindin (DTNBP1) gene expression in normal brain and in schizophrenic prefrontal cortex and midbrain. Arch Gen Psychiatry 2004; 61: 544–555.

    CAS  Article  Google Scholar 

  18. Weickert CS, Rothmond DA, Hyde TM, Kleinman JE, Straub RE . Reduced DTNBP1 (dysbindin-1) mRNA in the hippocampal formation of schizophrenia patients. Schizophr Res 2008; 98: 105–110.

    Article  Google Scholar 

  19. Talbot K, Eidem WL, Tinsley CL, Benson MA, Thompson EW, Smith RJ et al. Dysbindin-1 is reduced in intrinsic, glutamatergic terminals of the hippocampal formation in schizophrenia. J Clin Invest 2004; 113: 1353–1363.

    CAS  Article  Google Scholar 

  20. Bray NJ, Preece A, Williams NM, Moskvina V, Buckland PR, Owen MJ et al. Haplotypes at the dystrobrevin binding protein 1 (DTNBP1) gene locus mediate risk for schizophrenia through reduced DTNBP1 expression. Hum Mol Genet 2005; 14: 1947–1954.

    CAS  Article  Google Scholar 

  21. Camargo LM, Collura V, Rain JC, Mizuguchi K, Hermjakob H, Kerrien S et al. Disrupted in Schizophrenia 1 Interactome: evidence for the close connectivity of risk genes and a potential synaptic basis for schizophrenia. Mol Psychiatry 2007; 12: 74–86.

    CAS  Article  Google Scholar 

  22. Dermitzakis ET, Reymond A, Antonarakis SE . Conserved non-genic sequences—an unexpected feature of mammalian genomes. Nat Rev Genet 2005; 6: 151–157.

    CAS  Article  Google Scholar 

  23. Brune M . Schizophrenia—an evolutionary enigma? Neurosci Biobehav Rev 2004; 28: 41–53.

    Article  Google Scholar 

  24. Crespi B, Summers K, Dorus S . Adaptive evolution of genes underlying schizophrenia. Proc Biol Sci 2007; 274: 2801–2810.

    CAS  Article  Google Scholar 

  25. Voight BF, Kudaravalli S, Wen X, Pritchard JK . A map of recent positive selection in the human genome. PLoS Biol 2006; 4: e72.

    Article  Google Scholar 

  26. Yang Z . PAML 4: phylogenetic analysis by maximum likelihood. Mol Biol Evol 2007; 24: 1586–1591.

    CAS  Article  Google Scholar 

  27. MacCallum C, Hill E . Being positive about selection. PLoS Biol 2006; 4: e87.

    Article  Google Scholar 

  28. Thierry-Mieg D, Thierry-Mieg J . AceView: a comprehensive cDNA-supported gene and transcripts annotation. Genome Biol 2006; 7 (Suppl 1: S12): 11–14.

    Google Scholar 

  29. Jiang C, Zhao Z . Mutational spectrum in the recent human genome inferred by single nucleotide polymorphisms. Genomics 2006; 88: 527–534.

    CAS  Article  Google Scholar 

  30. Stephens M, Smith NJ, Donnelly P . A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 2001; 68: 978–989.

    CAS  Article  Google Scholar 

  31. Zhao Z, Yu N, Fu Y-X, Li W-H . Nucleotide variation and haplotype diversity in a 10-kb noncoding region in three continental human populations. Genetics 2006; 174: 399–409.

    CAS  Article  Google Scholar 

  32. Mutsuddi M, Morris DW, Waggoner SG, Daly MJ, Scolnick EM, Sklar P . Analysis of high-resolution HapMap of DTNBP1 (Dysbindin) suggests no consistency between reported common variant associations and schizophrenia. Am J Hum Genet 2006; 79: 903–909.

    CAS  Article  Google Scholar 

  33. Bandelt HJ, Forster P, Rohl A . Median-joining networks for inferring intraspecific phylogenies. Mol Biol Evol 1999; 16: 37–48.

    CAS  Article  Google Scholar 

  34. Williams NM, Preece A, Morris DW, Spurlock G, Bray NJ, Stephens M et al. Identification in 2 independent samples of a novel schizophrenia risk haplotype of the dystrobrevin binding protein gene (DTNBP1). Arch Gen Psychiatry 2004; 61: 336–344.

    CAS  Article  Google Scholar 

  35. 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 2004; 13: 2699–2708.

    CAS  Article  Google Scholar 

  36. Donohoe G, Morris DW, Clarke S, McGhee KA, Schwaiger S, Nangle JM et al. Variance in neurocognitive performance is associated with dysbindin-1 in schizophrenia: a preliminary study. Neuropsychologia 2007; 45: 454–458.

    Article  Google Scholar 

  37. Donohoe G, Morris DW, De Sanctis P, Magno E, Montesi JL, Garavan HP et al. Early visual processing deficits in dysbindin-associated schizophrenia. Biol Psychiatry 2008; 63: 484–489.

    Article  Google Scholar 

  38. Corvin A, Donohoe G, Nangle JM, Schwaiger S, Morris D, Gill M . A dysbindin risk haplotype associated with less severe manic-type symptoms in psychosis. Neurosci Lett 2008; 431: 146–149.

    CAS  Article  Google Scholar 

  39. Chubb JE, Bradshaw NJ, Soares DC, Porteous DJ, Millar JK . The DISC locus in psychiatric illness. Mol Psychiatry 2008; 13: 36–64.

    CAS  Article  Google Scholar 

  40. Di Pietro SM, Falcon-Perez JM, Tenza D, Setty SR, Marks MS, Raposo G et al. BLOC-1 interacts with BLOC-2 and the AP-3 complex to facilitate protein trafficking on endosomes. Mol Biol Cell 2006; 17: 4027–4038.

    CAS  Article  Google Scholar 

  41. Schweizer FE, Ryan TA . The synaptic vesicle: cycle of exocytosis and endocytosis. Curr Opin Neurobiol 2006; 16: 298–304.

    CAS  Article  Google Scholar 

  42. Talbot K, Cho DS, Ong WY, Benson MA, Han LY, Kazi HA et al. Dysbindin-1 is a synaptic and microtubular protein that binds brain snapin. Hum Mol Genet 2006; 15: 3041–3054.

    CAS  Article  Google Scholar 

  43. Ni X, Trakalo J, Valente J, Azevedo MH, Pato MT, Pato CN et al. Human p53 tumor suppressor gene (TP53) and schizophrenia: case–control and family studies. Neurosci Lett 2005; 388: 173–178.

    CAS  Article  Google Scholar 

  44. Thiselton DL, Vladimirov VI, Kuo PH, McClay J, Wormley B, Fanous A et al. AKT1 is associated with schizophrenia across multiple symptom dimensions in the Irish study of high density schizophrenia families. Biol Psychiatry 2008; 63: 449–457.

    CAS  Article  Google Scholar 

  45. Jeong H, Mason SP, Barabasi AL, Oltvai ZN . Lethality and centrality in protein networks. Nature 2001; 411: 41–42.

    CAS  Article  Google Scholar 

  46. Rizo J, Chen X, Arac D . Unraveling the mechanisms of synaptotagmin and SNARE function in neurotransmitter release. Trends Cell Biol 2006; 16: 339–350.

    CAS  Article  Google Scholar 

  47. Ruder C, Reimer T, Delgado-Martinez I, Hermosilla R, Engelsberg A, Nehring R et al. EBAG9 adds a new layer of control on large dense-core vesicle exocytosis via interaction with Snapin. Mol Biol Cell 2005; 16: 1245–1257.

    Article  Google Scholar 

  48. Ilardi JM, Mochida S, Sheng ZH . Snapin: a SNARE-associated protein implicated in synaptic transmission. Nat Neurosci 1999; 2: 119–124.

    CAS  Article  Google Scholar 

  49. Sudhof TC . The synaptic vesicle cycle: a cascade of protein-protein interactions. Nature 1995; 375: 645–653.

    CAS  Article  Google Scholar 

  50. Zhang Q, Pangrsic T, Kreft M, Krzan M, Li N, Sul JY et al. Fusion-related release of glutamate from astrocytes. J Biol Chem 2004; 279: 12724–12733.

    CAS  Article  Google Scholar 

  51. Rees ML, Lien CF, Gorecki DC . Dystrobrevins in muscle and non-muscle tissues. Neuromuscul Disord 2007; 17: 123–134.

    Article  Google Scholar 

  52. Rando TA . The dystrophin-glycoprotein complex, cellular signaling, and the regulation of cell survival in the muscular dystrophies. Muscle Nerve 2001; 24: 1575–1594.

    CAS  Article  Google Scholar 

  53. Mehler MF . Brain dystrophin, neurogenetics and mental retardation. Brain Res Rev 2000; 32: 277–307.

    CAS  Article  Google Scholar 

  54. Blake DJ, Nawrotzki R, Loh NY, Gorecki DC, Davies KE . beta-dystrobrevin, a member of the dystrophin-related protein family. Proc Natl Acad Sci USA 1998; 95: 241–246.

    CAS  Article  Google Scholar 

  55. Culligan K, Ohlendieck K . Diversity of the brain dystrophin-glycoprotein complex. J Biomed Biotechnol 2002; 2: 31–36.

    CAS  Article  Google Scholar 

  56. Maden M . Retinoic acid in the development, regeneration and maintenance of the nervous system. Nat Rev Neurosci 2007; 8: 755–765.

    CAS  Article  Google Scholar 

  57. Mey J, McCaffery P . Retinoic acid signaling in the nervous system of adult vertebrates. Neuroscientist 2004; 10: 409–421.

    CAS  Article  Google Scholar 

  58. Palha JA, Goodman AB . Thyroid hormones and retinoids: a possible link between genes and environment in schizophrenia. Brain Res Rev 2006; 51: 61–71.

    CAS  Article  Google Scholar 

  59. Rao ML, Kolsch H . Effects of estrogen on brain development and neuroprotection—implications for negative symptoms in schizophrenia. Psychoneuroendocrinology 2003; 28 (Suppl 2): 83–96.

    CAS  Article  Google Scholar 

  60. Li XH, Kakkad B, Ong DE . Estrogen directly induces expression of retinoic acid biosynthetic enzymes, compartmentalized between the epithelium and underlying stromal cells in rat uterus. Endocrinology 2004; 145: 4756–4762.

    CAS  Article  Google Scholar 

  61. Blitzer RD, Iyengar R, Landau EM . Postsynaptic signaling networks: cellular cogwheels underlying long-term plasticity. Biol Psychiatry 2005; 57: 113–119.

    CAS  Article  Google Scholar 

  62. Sullivan JM . Cellular and molecular mechanisms underlying learning and memory impairments produced by cannabinoids. Learn Mem 2000; 7: 132–139.

    CAS  Article  Google Scholar 

  63. Hakak Y, Walker JR, Li C, Wong WH, Davis KL, Buxbaum JD et al. Genome-wide expression analysis reveals dysregulation of myelination-related genes in chronic schizophrenia. Proc Natl Acad Sci USA 2001; 98: 4746–4751.

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We regret that many DTNBP1 studies, especially association studies, have not been cited in this review because of our focus on gene feature and network analysis. This work was supported by a NARSAD Young Investigator Award and a Jeffress Trust grant to ZZ and a research grant (R01MH41953) to KSK/BPR.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Z Zhao.

Additional information

Supplementary Information accompanies the paper on the Molecular Psychiatry website (http://www.nature.com/mp)

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Guo, A., Sun, J., Riley, B. et al. The dystrobrevin-binding protein 1 gene: features and networks. Mol Psychiatry 14, 18–29 (2009). https://doi.org/10.1038/mp.2008.88

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/mp.2008.88

Keywords

  • DTNBP1
  • schizophrenia
  • splicing
  • haplotype
  • protein–protein interaction
  • gene network

Further reading

Search

Quick links