Novak G, Kim D, Seeman P, Tallerico T
Department of Pharmacology, Medical Sciences Building, University of Toronto, Room 4344, Medical Science Building, 8 Taddle Creek Road, Ontario, M5S 1A8, Toronto, Canada.
Brain Res Mol Brain Res. 2002 Nov 15;107(2):183-9. doi: 10.1016/s0169-328x(02)00492-8.
Schizophrenia is a major psychiatric disorder which is hypothesized to result from abnormal neurodevelopment or neural changes in adulthood and possibly associated with altered gene expression. To search for genes overexpressed in schizophrenia, cDNA library subtractive hybridization experiments between post-mortem human frontal cerebral cortices from schizophrenia individuals and neurological controls were carried out. One of the genes over-expressed in schizophrenia was identified as Nogo (also known as reticulon 4, RTN4, NI 250, or RTN-X), a myelin-associated protein which inhibits the outgrowth of neurites and nerve terminals. The elevated expression of Nogo mRNA in schizophrenia was confirmed by quantitative reverse transcription-polymerase chain reaction studies: 16.5 pg Nogo cDNA/microg total RNA in schizophrenia, and 10.2 pg Nogo cDNA/microg total RNA in controls (n=7; P=0.01, t-test for n<30). To identify possible polymorphisms in this gene, the Nogo nucleotide sequence was determined in a series of schizophrenia and control samples. The Nogo mRNA was found to contain a CAA insert polymorphism in the 3'-untranslated region. The prevalence of individuals homozygous for this CAA insert was significantly higher in schizophrenia compared to controls in genomic DNA samples extracted from post-mortem brain and blood samples: 17/81 or 21% in schizophrenia and 2/61 or 3% in controls (P=0.0022, chi(2)- and Fisher's exact-tests). Because the 3'-untranslated regions of eukaryotic genes are known to regulate gene expression, the increased frequency of the Nogo CAA insert in schizophrenia may contribute to abnormal regulation of Nogo gene expression, and may indicate a role for Nogo in disturbed neurodevelopment in schizophrenia.
精神分裂症是一种主要的精神疾病，据推测其源于成年期异常的神经发育或神经变化，并且可能与基因表达改变有关。为了寻找在精神分裂症中过表达的基因，对精神分裂症患者和神经学对照者的死后人类额叶大脑皮质进行了cDNA文库消减杂交实验。在精神分裂症中过表达的基因之一被鉴定为Nogo（也称为网蛋白4、RTN4、NI 250或RTN-X），一种抑制神经突和神经末梢生长的髓鞘相关蛋白。通过定量逆转录-聚合酶链反应研究证实了精神分裂症中Nogo mRNA的表达升高：精神分裂症患者中为16.5 pg Nogo cDNA/μg总RNA，对照组中为10.2 pg Nogo cDNA/μg总RNA（n = 7；P = 0.01，n < 30时的t检验）。为了鉴定该基因中可能的多态性，在一系列精神分裂症和对照样本中测定了Nogo核苷酸序列。发现Nogo mRNA在3'-非翻译区含有一个CAA插入多态性。在从死后大脑和血液样本中提取的基因组DNA样本中，精神分裂症患者中该CAA插入纯合子个体的患病率显著高于对照组：精神分裂症患者中为17/81或21%，对照组中为2/61或3%（P = 0.0022，卡方检验和Fisher精确检验）。由于已知真核基因的3'-非翻译区调节基因表达，精神分裂症中Nogo CAA插入频率的增加可能导致Nogo基因表达的异常调节，并可能表明Nogo在精神分裂症中神经发育紊乱中起作用。
