Abstract
Genetic variations in the human dysbindin-1 gene (DTNBP1) have been associated with schizophrenia. As a result of alternative splicing, the human DTNBP1 gene generates at least three distinct protein isoforms, dysbindin-1A, -1B and -1C. Significant effort has focused on dysbindin-1A, an important player in multiple steps of neurodevelopment. However, the other isoforms, dysbindin-1B and dysbindin-1C have not been well characterized. Nor have been associated with human diseases. Here we report an increase in expression of DTNBP1b mRNA in patients with paranoid schizophrenia as compared with healthy controls. A single-nucleotide polymorphism located in intron 9, rs117610176, has been identified and associated with paranoid schizophrenia, and its C allele leads to an increase of DTNBP1b mRNA splicing. Our data show that different dysbindin splicing isoforms exhibit distinct subcellular distribution, suggesting their distinct functional activities. Dysbindin-1B forms aggresomes at the perinuclear region, whereas dysbindin-1A and -1C proteins exhibit diffused patterns in the cytoplasm. Dysbindin-1A interacts with dysbindin-1B, getting recruited to the aggresome structure when co-expressed with dysbindin-1B. Moreover, cortical neurons over-expressing dysbindin-1B show reduction in neurite outgrowth, suggesting that dysbindin-1B may interfere with dysbindin-1A function in a dominant-negative manner. Taken together, our study uncovers a previously unknown association of DTNBP1b expression with schizophrenia in addition to its distinct biochemical and functional properties.
Highlights
Schizophrenia is one of the most devastating psychiatric disorders, affecting about 1% of the general population in their lifetime [1]
We have examined the differences in expression of all three dysbindin-1 mRNA isoforms between patients with paranoid schizophrenia and healthy control subjects, dysbindin-1B mRNA is elevated among the patients
These results suggest that the expression of DTNBP1b mRNA was increased in patients with paranoid schizophrenia
Summary
Schizophrenia is one of the most devastating psychiatric disorders, affecting about 1% of the general population in their lifetime [1]. The association of gene encoding dysbindin-1 protein (DTNBP1) with schizophrenia has been repeatedly reported in multiple independent case-control studies [2,3,4,5,6,7,8,9,10,11,12,13,14,15]. No GWA studies have confirmed the association till reduced expression of dysbindin-1 mRNA and proteins has been observed in the brains of schizophrenia patients, including the dorsolateral prefrontal cortex [16] and the cerebral cortex [9]. Reduced dysbindin-1 protein levels have been found in a specific area of the hippocampus and immortalized lymphocytes of schizophrenia patients [17,18,19]. Dysbindin-1 contributes to neurite outgrowth, dendritic spine formation and neural differentiation [43,44,45,46]
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