Association of NPAS3 exonic variation with schizophrenia
Association of NPAS3 exonic variation with schizophrenia
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DOI：
10.1016/j.schres.2010.04.002
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发表时间：
2010-07-01
影响因子：
4.5
通讯作者：
Cox, Diane W.
中科院分区：
文献类型：
--
作者：
Macintyre, Georgina;Alford, Tyler;Cox, Diane W.
背景：我们之前将神经元 PAS3 (NPAS3) 基因确定为精神分裂症的候选基因。一对患有精神分裂症的母女是易位 t(9;14)(q34;q13) 的携带者，这种易位会破坏 NPAS3 基因。该基因位于 14q13，在各种连锁研究中，该区域与精神分裂症和双相情感障碍有关。 NPAS3 属于基本螺旋-环-螺旋 Per-Arnt-Sim (bHLH-PAS) 转录因子家族，参与多种过程，包括细胞分化和昼夜节律的调节以及神经系统的发育和功能。方法：对精神分裂症患者 DNA 中编码 NPAS3 的 12 个外显子进行测序。 NPAS3 变异在外显子 6 和 12 中被发现，最初仅在 12 名患者中发现。然后在 83 名患者和 83 名对照者中对这两个外显子进行测序。结果和结论：在对照中也发现了 NPAS3 的三种常见变异，显示与精神分裂症呈正相关（NM_001164749：rs12434716，c.1654G>C，p=0.009；rs10141940，c.2208C>T，p= 0.01；rs10142034，c.2262C>G，p = 0.01）。 c.1654G>C 变体导致 p.Ala552Pro 发生变化，并可能直接影响 NPAS3 蛋白功能。或者，这三个 SNP 可能会影响 NPAS3 转录本的剪接，因为它们各自位于推定的外显子剪接增强子 (ESE) 基序 (ESEFinder) 内。在三名患者中鉴定出的 c.726C>T 变体位于 ESE 元件中，预计会降低基序的功能。在对照中发现的其他变体包括 c.2089G>A (p.Gly697Ser) 和 c.2097T>C。我们对潜在缺陷 NPAS3 变体的识别支持了最近的研究，这些研究表明 NPAS3 通路的扰动与神经发生受损和精神病有关。 (C) 2010 Elsevier B.V. 保留所有权利。
Background: We previously identified the neuronal PAS3 (NPAS3) gene as a candidate gene for schizophrenia. A mother and daughter, both with schizophrenia, were carriers of a translocation, t(9;14)(q34;q13), that disrupts the NPAS3 gene. The gene is located at 14q13, a region implicated in schizophrenia and bipolar disorder in various linkage studies. NPAS3 belongs to the basic helix-loop-helix Per-Arnt-Sim (bHLH-PAS) transcription factor family, involved in diverse processes including the regulation of cell differentiation and circadian rhythms, and the development and function of the nervous system.Methods: The 12 exons encoding NPAS3 were sequenced in DNA from individuals with schizophrenia. NPAS3 variants were identified in exons 6 and 12, initially in 12 patients only. These two exons were then sequenced in 83 patients and 83 controls.Results and conclusion: Three common variants of NPAS3, also found in controls, showed a positive association with schizophrenia (NM_001164749: rs12434716, c.1654G>C, p=0.009; rs10141940, c.2208C>T, p = 0.01; rs10142034, c.2262C>G, p = 0.01). The c.1654G>C variant, results in an p.Ala552Pro change and may affect NPAS3 protein function directly. Alternatively, the three SNPs may affect the splicing of NPAS3 transcripts, as they are each located within putative exonic splicing enhancer (ESE) motifs (ESEFinder). A c.726C>T variant, identified in three patients, is located in an ESE element and is predicted to reduce the function of the motif. Other variants, identified in controls, included c.2089G>A (p.Gly697Ser) and c.2097T>C. Our identification of potentially defective NPAS3 variants supports recent studies that implicate perturbations in NPAS3 pathways in impaired neurogenesis and psychosis. (C) 2010 Elsevier B.V. All rights reserved.