Disease relevance of DTNBP1

• Dysbindin was identified as a dystrobrevin-binding protein potentially involved in the pathogenesis of muscular dystrophy [1].

Psychiatry related information on DTNBP1

• We analyzed seven previously tested DTNBP1 single-nucleotide polymorphisms (SNPs) in a cohort of 524 individuals with schizophrenia or schizoaffective disorder and 573 control subjects [2].
• Several disposition genes for schizophrenia (DTNBP1, NRG1, G72) were identified, whereas evidence for specific disposition genes in bipolar disorder is more limited [3].
• Association of the dysbindin gene with bipolar affective disorder [4].

High impact information on DTNBP1

• Hermansky-Pudlak syndrome type 7 (HPS-7) results from mutant dysbindin, a member of the biogenesis of lysosome-related organelles complex 1 (BLOC-1) [5].
• Although no mutations in the dysbindin gene have been found, the recent identification of a specific risk haplotype in independent samples provides further evidence that dysbindin is a possible schizophrenia susceptibility gene [6].
• Schizophrenia genetics: dysbindin under the microscope [6].
• 3. Dysbindin-1 is best known as dystrobrevin-binding protein 1 (DTNBP1) and may thus be associated with the dystrophin glycoprotein complex found at certain postsynaptic sites in the brain [7].
• Human dysbindin (DTNBP1) gene expression in normal brain and in schizophrenic prefrontal cortex and midbrain [8].

Biological context of DTNBP1

• Currently, the weight of evidence supports NRG1 and DTNBP1 as schizophrenia susceptibility loci, though work remains before we understand precisely how genetic variation at each locus confers susceptibility and protection [9].
• Identification in 2 independent samples of a novel schizophrenia risk haplotype of the dystrobrevin binding protein gene (DTNBP1) [10].
• OBJECTIVES: To confirm DTNBP1 as a schizophrenia susceptibility gene, to identify and replicate specific risk and protective haplotypes, and to explore relationships between DTNBP1 and the phenotype [10].
• We genotyped 10 single-nucleotide polymorphisms (SNPs) in DTNBP1 that were used in the original report of association, plus rs2619538 (SNP 'A') in the putative promoter region, which has also been associated with schizophrenia [11].
• However, the linkage disequilibrium (LD) among the SNPs in DTNBP1 as well as the pattern of significant SNP-schizophrenia association was complex [12].

Anatomical context of DTNBP1

• In the present study, we show that a defined schizophrenia risk haplotype tags one or more cis-acting variants that results in a relative reduction in DTNBP1 mRNA expression in human cerebral cortex [13].
• These suggest an involvement of DTNBP1 in the prefrontal cortex and cognitive functions mediated by interaction with neurotransmitter systems, in particular glutamate [14].
• RESULTS: Dysbindin mRNA was detected in the frontal cortex, temporal cortex, hippocampus, caudate, putamen, nucleus accumbens, amygdala, thalamus, and midbrain of the adult brain [8].
• Furthermore, suppression of dysbindin expression in PC12 cells resulted in an increase of the expression of SNAP25, which plays an important role in neurotransmitter release, and increased the release of dopamine [15].
• In situ hybridization analysis showed the mRNA expression of dysbindin in the mouse substantia nigra [15].

Associations of DTNBP1 with chemical compounds

• 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 [16].
• Immunoprecipitation of endogenous dysbindin from brain or muscle resulted in robust co-immunoprecipitation of the pallidin subunit of BLOC-1 but no specific co-immunoprecipitation of dystrobrevin isoforms [1].
• These data suggest that dysbindin might regulate the dopamine release of the dopaminergic system via modulation of the expression of SNAP25 [15].
• This study shows that the DTNBP1 gene modulates the effects of both the atypical antipsychotic clozapine and the typical antipsychotic haloperidol [17].
• DTNBP seems to have an effect on short-term clinical response to citalopram [18].

Physical interactions of DTNBP1

• Dysbindin structural homologue CK1BP is an isoform-selective binding partner of human casein kinase-1 [19].

Regulatory relationships of DTNBP1

• The thrombin-mediated cleavage of protein S could be inhibited by HPS 7 [20].
• The calcium-dependent binding of protein S to phospholipid vesicles as well as the protein C cofactor activity was inhibited by HPS 7 [20].

Other interactions of DTNBP1

• On the basis of corrected P-values from single- and multilocus transmission distortion tests our analysis provides no support for a contribution of G72, NRG1 or DTNBP1 in the tested samples [21].
• The identification of these loci together with advances in genetic technology, especially the characterisation of polymorphisms, the understanding of haplotypes and the development of statistical methods, has lead to the identification of several plausible susceptibility genes, including neuregulin 1, proline dehydrogenase and dysbindin [22].
• We used a case control design to analyze single nucleotide polymorphisms (SNPs) and insertion/deletion variants affecting AT-rich domains in both the DTNBP1 and JARID2 genes [23].
• Patients with schizophrenia had statistically significantly reduced dysbindin mRNA levels in multiple layers of the dorsolateral prefrontal cortex, whereas synaptophysin, spinophilin, and cyclophilin mRNA levels were unchanged [8].
• Support for association of schizophrenia with genetic variation in the 6p22.3 gene, dysbindin, in sib-pair families with linkage and in an additional sample of triad families [24].

Analytical, diagnostic and therapeutic context of DTNBP1

• On the basis of sequence alignments, CK1BP was a structural homologue of the acidic domain of dysbindin, a component of the dystrophin-associated protein complex and the biogenesis of lysosome-related organelles complex-1 [19].
• So far, traditional linkage mapping studies have not definitively identified specific disease genes for neuropsychiatric disorders, although some potential candidates have been identified via these methods (e.g. the dysbindin gene in schizophrenia; Straub et al., 2002; Schwab et al., 2003) [25].
• The enzyme was separated from venom by gel filtration on Sephadex G-100 superfine and chromatography on agarose HPS-7 and phenyl-agarose [26].

References