Downregulation of myelination, energy, and translational genes in Menkes disease brain
Downregulation of myelination, energy, and translational genes in Menkes disease brain
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DOI：
10.1016/j.ymgme.2005.04.007
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发表时间：
2005-08-01
影响因子：
3.8
通讯作者：
Kaler, SG
中科院分区：
文献类型：
--
作者：
Liu, PC;Chen, YW;Kaler, SG
门克斯病 (MD) 是一种 X 连锁隐性神经退行性疾病，由铜转运 p 型 ATP 酶 (ATP7A) 突变引起，该酶通常将铜输送到中枢神经系统。 MID 神经退行性变的确切原因尚不清楚。我们假设，具有致命性 ATP7A 突变的 MID 患者的基因表达变化将表明与发育中大脑中铜缺乏的影响相关的病理生理级联反应。为了检验这一假设，使用 Affymetrix 人类基因组 U95 基因芯片上排列的 12,000 个基因的寡核苷酸探针对来自 6 个月龄死亡 MD 患者死后大脑皮层和小脑的荧光标记初级 cRNA 以及年龄、性别和种族匹配的正常对照大脑进行表达谱分析。先证者大脑的组织病理学分析显示神经元完整性得以保存并且没有缺氧影响。然而，脑脊液和脑铜水平低于正常，表达谱鉴定出超过 350 个已知的失调基因。对于通过定量 RT-PCR 分析的基因子集（约 12%），正确的交叉验证率为 88%。皮层和小脑中的三十个已知基因都发生了改变。主要发现是与髓鞘形成、能量代谢和翻译相关的基因下调。小脑对铜缺乏更为敏感。由爱思唯尔公司出版
Menkes disease (MD) is an X-linked recessive neurodegenerative disorder caused by mutations in a copper-transporting p-type ATPase (ATP7A) that normally delivers copper to the central nervous system. The precise reasons for neurodegeneration in MID are poorly understood. We hypothesized that gene expression changes in a MID patient with a lethal ATP7A mutation would indicate pathophysiological cascades relevant to the effects of copper deficiency in the developing brain. To test this hypothesis, oligonucleotide probes for 12,000 genes arrayed on Affymetrix Human Genome U95 GeneChips were used for expression profiling of fluorescently labeled primary cRNAs from post-mortem cerebral cortex and cerebellum of a MD patient who died at 6 months of age and a normal control brain matched for age, gender, and race. Histopathologic analysis of the proband's brain showed preservation of neuronal integrity and no hypoxic effects. However, cerebrospinal fluid and brain copper levels were subnormal, and expression profiling identified over 350 known dysregulated genes. For a subset of genes (approximate to 12%) analyzed by quantitative RT-PCR, the correct cross-validation rate was 88%. Thirty known genes were altered in both cortex and cerebellum. Downregulation of genes involved in myelination, energy metabolism, and translation was the major finding. The cerebellum was more sensitive to copper deficiency. Published by Elsevier Inc.