title: Increased dysbindin-1B isoform expression in schizophrenia and its propensity in aggresome formation.
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.
authors.affiliation: National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Tsinghua University, Beijing, China; Department of Medical Genetics, School of Basic Medical Sciences, Capital Medical University, Beijing, China.
authors.forename: Yiliang
authors.initials: Y
authors.lastname: Xu
authors.affiliation: National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Tsinghua University , Beijing, China.
authors.forename: Yuhui
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Medical Genetics, School of Basic Medical Sciences, Capital Medical University, Beijing, China; The State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Haihong
authors.initials: H
authors.lastname: Ye
authors.affiliation: The State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences , Beijing, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhu
authors.affiliation: The State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences , Beijing, China.
authors.forename: Jianghong
authors.initials: J
authors.lastname: Liu
authors.affiliation: National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Tsinghua University , Beijing, China.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Wu
authors.affiliation: National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Tsinghua University , Beijing, China.
authors.forename: Le
authors.initials: L
authors.lastname: Wang
authors.affiliation: National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Tsinghua University , Beijing, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: He
authors.affiliation: National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Tsinghua University , Beijing, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Shen
authors.affiliation: The State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China; Department of Neurology, Center of Genetic Medicine, Lurie Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Jane Y
authors.initials: JY
authors.lastname: Wu
authors.affiliation: National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Tsinghua University , Beijing, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Xu
keywords: dysbindin-1; neurite outgrowth; protein aggregation; schizophrenia