The Alternative Splicing Of A Schizophrenia Susceptibility Gene Dysbindin In Regulating Its Neurodevelopmental Function And The Association Study Of The Monoamine Oxidase A (MAOA)Gene With Paranoid Schizophrenia Among A Chinese Population

Schizophrenia is one of the most severe mental disorders, with the lifetime prevalence about1%in the total population. This disorder always suffers the youth, and brings heavy economical and social burdens to families and societies. Schizophrenia is considered as a typical complex disorder, with a high heritability up to80%. Many candidate genes are considered susceptible to schizophrenia through association analysis and linkage studies, but their exact funtions need further validated.In the first part of our studies, we focused on the role of alternative spliced isoforms of dysbindin, a schizophrenia susceptibility gene, in regulating its neurobiological function. Consistent with previous studies, the DTNBP1(dysbindin) gene was associated with paranoid schizophrenia in the Chinese Han population in our studies. We found that the expression of DTNBP1b, one of the dysbindin transcripts, was increased in the peripheral blood lymphocytes of the patients with paranoid schizophrenia. Dysbindin-B showed a different subcellular distribution from isofoms A and C, aggregating at the perinuclear region when overexpressed in various cell lines and primary cultured cortical neurons. The aggregation of dysbindin-B was characterized as a structure called "aggresome" by its perinuclear location at the MTOC (microtubule organizing center) and staining evidences with different markers. Proteasome inhibitor, MG132, treatment on dysbindin-A, resulted in an accumulation of soluble fraction, suggesting a PEST-sequence involved in proteasomal degradation pathway. In contrast, dysbindin-B which is lack of a PEST domain at the C-terminus, showed reduced sensitivity to MG132. Purified dysbindin-A was found to form homophilic binding with itself in vitro. An interaction was also occurred between dysbindin-A and B. When co-transfected with dysbindin-B in cells, most dysbindin-A was recruited to the aggresome structure, which is likely induced by the interaction with dysbindin-B. Finally, we found that disbindin-B inhibited neurite outgrowth of cortical neurons. Thus, dysbindin-B probably acts in a dominant-negative manner to regulate the normal neurobiological function of dysbindin. Our study further verified that dysbindin may play a critical role in the neurodevelopmental etiology of schizophrenia.In the second part, the association of the MAOA gene with paranoid schizophrenia was studied. Monoamine oxidase A (MAOA) is the enzyme responsible for degradation of several monoamines, such as dopamine and serotonin which are considered as two of the most important neurotransmitters involved in the pathophysiology of schizophrenia. To study a possible role of MAOA in conferring susceptibility to schizophrenia, the present study genotyped the variable number of tandem repeat (VNTR) polymorphism and41SNPs across this gene among555unrelated patients with paranoid schizophrenia and567unrelated healthy controls. Quantitative real-time PCR analysis was employed to quantify expression of MAOA mRNA in73drug-free patients. While none of these genotyped DNA markers showed allelic association with paranoid schizophrenia, haplotypic association was found for the VNTR-rs6323, VNTR-rs1137070and VNTR-rs6323-rs1137070haplotypes in female subjects. Nevertheless, no significant change of the expression of MAOA mRNA was detected in either female or male patients with paranoid schizophrenia. Our study suggests that the interaction between genetic variants within the MAOA gene may contribute to an increased risk of paranoid schizophrenia, but the precise mechanism needs further investigation.