Dysbindin (DTNBP1) and the Biogenesis of Lysosome-Related Organelles Complex 1 (BLOC-1): Main and Epistatic Gene Effects Are Potential Contributors to Schizophrenia Susceptibility

Neuropsychiatric Genetics Group, Department of Psychiatry and Institute of Molecular Medicine, Trinity College, Dublin, Ireland. /
Biological psychiatry (Impact Factor: 9.47). 02/2008; 63(1):24-31. DOI: 10.1016/j.biopsych.2006.12.025
Source: PubMed

ABSTRACT The DTNBP1 gene, encoding dysbindin, has been strongly implicated in schizophrenia (SZ) susceptibility by a series of independent genetic association and gene expression studies. Among its known functions, dysbindin is part of a protein complex, termed the biogenesis of lysosome-related organelles complex 1 (BLOC-1), the molecular components of which might be involved in the regulation of vesicular trafficking and dendrite branching.
A systematic investigation of the other seven BLOC-1 genes (MUTED, PLDN, CNO, SNAPAP, BLOC1S1, BLOC1S2, and BLOC1S3) for evidence of association with SZ was undertaken in a sample of 373 SZ cases and 812 control subjects. Possible epistasis between combinations of BLOC-1 genes, including DTNBP1, was tested with a novel method of investigating for gene-gene interaction. Quality control measures were incorporated into genotyping strategy, and all results were corrected for multiple testing to prevent false positive results.
We identified significant evidence of association between BLOC1S3 and SZ (odds ratio = 1.45, confidence interval = 1.13-1.86, p = .0028, corrected p = .0389). We also report evidence for epistatic interaction between DTNBP1 and MUTED contributing to SZ in the absence of a significant main effect at MUTED (p = .0009, corrected p = .0252). Single marker and epistasis results remained significant after correction for multiple testing.
Together these data provide evidence for the involvement of the BLOC-1 protein complex in SZ pathogenesis.

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Available from: Kevin John Murphy, Aug 11, 2015
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    • "The altered ultrastructure of hippocampal synaptic vesicles might cause reduced neurotransmission and thereafter the schizophrenia-like symptoms observed in sdy mice (Chen et al., 2008; Feng et al., 2008; Wang et al., 2014). However, except for DTNBP1 and BLOC1S3, genes encoding other BLOC-1 subunits have no significant association with schizophrenia although an epistatic interaction between DTNBP1 and MUTED might exist (Morris et al., 2008). Currently, there is no support for MUTED as a susceptibility gene for schizophrenia (Gerrish et al., 2009). "
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    ABSTRACT: The large dense-core vesicle (LDCV), a type of lysosome-related organelle, is involved in the secretion of hormones and neuropeptides in specialized secretory cells. The granin family is a driving force in LDCV biogenesis, but the machinery for granin sorting to this biogenesis pathway is largely unknown. The mu mutant mouse, which carries a spontaneous null mutation on the Muted gene (also known as Bloc1s5) that encodes a subunit of lysosome-related organelles complex-1 (BLOC-1), is a mouse model of Hermansky-Pudlak syndrome. We here found that LDCVs were enlarged in mu adrenal chromaffin cells. Chromogranin A (CgA) was increased in mu adrenals and muted-knockdown cells. The increased CgA in mu mice was likely due to the failure of its sorting-out, which impairs LDCV maturation and docking. In mu chromaffin cells, the size of readily releasable pool and the vesicle release frequency were reduced. Our studies suggest that the muted protein is involved in the sorting-out of CgA during the biogenesis of LDCVs.
    Journal of Cell Science 02/2015; 128(7). DOI:10.1242/jcs.161414 · 5.33 Impact Factor
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    • "Consistent with such a role in the nervous system, both Dysbindin and Snapin appear to function in synaptic vesicle trafficking and may be involved in other synaptic membrane trafficking pathways. Interestingly, another component of the BLOC-1 complex, Muted, has recently been associated with schizophrenia (Morris et al., 2008; Ryder and Faundez, 2009). These findings underscore the intriguing possibility that defective synaptic membrane trafficking through components of the BLOC-1 complex in the context of homeostatic synaptic plasticity may contribute to the etiology of complex neuropsychiatric diseases like schizophrenia. "
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    ABSTRACT: Homeostatic signaling systems are ubiquitous forms of biological regulation, having been studied for hundreds of years in the context of diverse physiological processes including body temperature and osmotic balance. However, only recently has this concept been brought to the study of excitatory and inhibitory electrical activity that the nervous system uses to establish and maintain stable communication. Synapses are a primary target of neuronal regulation with a variety of studies over the past 15 years demonstrating that these cellular junctions are under bidirectional homeostatic control. Recent work from an array of diverse systems and approaches has revealed exciting new links between homeostatic synaptic plasticity and a variety of seemingly disparate neurological and psychiatric diseases. These include autism spectrum disorders, intellectual disabilities, schizophrenia, and Fragile X Syndrome. Although the molecular mechanisms through which defective homeostatic signaling may lead to disease pathogenesis remain unclear, rapid progress is likely to be made in the coming years using a powerful combination of genetic, imaging, electrophysiological, and next generation sequencing approaches. Importantly, understanding homeostatic synaptic plasticity at a cellular and molecular level may lead to developments in new therapeutic innovations to treat these diseases. In this review we will examine recent studies that demonstrate homeostatic control of postsynaptic protein translation, retrograde signaling, and presynaptic function that may contribute to the etiology of complex neurological and psychiatric diseases.
    Frontiers in Cellular Neuroscience 11/2013; 7:223. DOI:10.3389/fncel.2013.00223 · 4.18 Impact Factor
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    • "The first two types of studies mentioned above (i and ii) have been discussed in recent reviews (Schwab and Wildenauer, 2009; Talbot et al., 2009). In short: large-scale genetic studies using a case-control design have failed to demonstrate genome-wide significance for any association between individual common variants in DTNBP1 and schizophrenia in the general population of European ancestry or African–Americans (Sanders et al., 2008; Shi et al., 2009); although it should be noted that these studies have not been designed to explore potential genetic heterogeneity (Maher et al., 2010), epistatic interactions between variants in two or more genes (Edwards et al., 2008; Morris et al., 2008), interactions between genetic variants and environmental factors (Nicodemus et al., 2008) or the possibility that the genetic link between DTNBP1 and the disease might be restricted to few families [reviewed by Psychiatric GWAS Consortium Steering Committee (2009)]. Nevertheless, decreased protein levels have been observed in hippocampus and prefrontal cortex of post-mortem brain samples from schizophrenic patients (Talbot et al., 2004; Tang et al., 2009a; Talbot et al., 2011), notably much more often than expected from the frequency of the allelic variants being considered as candidate risk factors of the disease. "
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    ABSTRACT: Dysbindin (also known as dysbindin-1 or dystrobrevin-binding protein 1) was identified 10 years ago as a ubiquitously expressed protein of unknown function. In the following years, the protein and its encoding gene, DTNBP1, have become the focus of intensive research owing to genetic and histopathological evidence suggesting a potential role in the pathogenesis of schizophrenia. In this review, we discuss published results demonstrating that dysbindin function is required for normal physiology of the mammalian central nervous system. In tissues other than brain and in non-neuronal cell types, the protein has been characterized as a stable component of a multi-subunit complex, named BLOC-1 (biogenesis of lysosome-related organelles complex-1), which has been implicated in intracellular protein trafficking and the biogenesis of specialized organelles of the endosomal-lysosomal system. In the brain, however, dysbindin has been proposed to associate into multiple complexes with alternative binding partners, and to play a surprisingly wide variety of functions including transcriptional regulation, neurite and dendritic spine formation, synaptic vesicle biogenesis and exocytosis, and trafficking of glutamate and dopamine receptors. This puzzling array of molecular and functional properties ascribed to the dysbindin protein from brain underscores the need of further research aimed at ascertaining its biological significance in health and disease.
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