PDE4B polymorphisms and decreased PDE4B expression are associated with schizophrenia
PDE4B polymorphisms and decreased PDE4B expression are associated with schizophrenia
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DOI：
10.1016/j.schres.2008.01.029
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发表时间：
2008-04-01
影响因子：
4.5
通讯作者：
Menniti, Frank S.
中科院分区：
文献类型：
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作者：
Fatemi, S. Hossein;King, David P.;Menniti, Frank S.
精神分裂症具有复杂的遗传基础，并且已经确定了许多候选基因的变异，这些变异赋予了发展该疾病的风险。我们报告在目前的研究中，几个单核苷酸多态性（SNPs）和两个SNP单倍型在PDE 4 B与精神分裂症的发病率增加在两个大的高加索人和非洲裔美国人患者的人群。与精神分裂症相关的PDE 4 B中的SNP发生在关键剪接点附近的内含子序列中，该关键剪接点引起具有不同调节和功能的PDE 4 B同种型的表达。我们还观察到特定的减少磷酸二酯酶4 B（PDE 4 B）isofon-ns在脑组织中获得尸检诊断为精神分裂症和双相情感障碍患者。PDE 4 B代谢失活第二信使cAMP以调节整个脑中神经元的细胞内信号传导。因此，目前的观察结果表明，由PDE 4 B介导的细胞内信号传导的失调是精神分裂症和双相情感障碍的原因和表达中的一个重要因素，并且靶向PDE 4 B调节的信号传导途径可能产生新的疗法来治疗这些疾病的整体。(C)2008 Elsevier B. V.保留所有权利。
Schizophrenia has a complex genetic underpinning and variations in a number of candidate genes have been identified that confer risk of developing the disorder. We report in the present studies that several single nucleotide polymorphisms (SNPs) and a two-SNP haplotype in PDE4B are associated with an increased incidence of schizophrenia in two large populations of Caucasian and African American patients. The SNPs in PDE4B associated with schizophrenia occur in intronic sequences in the vicinity of a critical splice junction that gives rise to the expression of PDE4B isoforms with distinct regulation and function. We also observed specific decreases in phosphodiesterase 4B (PDE4B) isofon-ns in brain tissue obtained postmortem from patients diagnosed with schizophrenia and bipolar disorder. PDE4B metabolically inactivates the second messenger cAMP to regulate intracellular signaling in neurons throughout the brain. Thus, the present observations suggest that dysregulation of intracellular signaling mediated by PDE4B is a significant factor in the cause and expression, respectively, of schizophrenia and bipolar disorder and that targeting PDE4B-regulated signaling pathways may yield new therapies to treat the totality of these disorders. (C) 2008 Elsevier B.V. All rights reserved.