Variations in the progranulin gene affect global gene expression in frontotemporal lobar degeneration
Variations in the progranulin gene affect global gene expression in frontotemporal lobar degeneration
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DOI：
10.1093/hmg/ddn023
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发表时间：
2008-05-15
影响因子：
3.5
通讯作者：
Lee, Virginia M. -Y.
中科院分区：
文献类型：
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作者：
Chen-Plotkin, Alice S.;Geser, Felix;Lee, Virginia M. -Y.
额颞叶变性是一种致命的神经退行性疾病，会导致行为、执行功能，有时还包括语言能力的逐渐下降。其疾病机制仍知之甚少。然而，最近DNA和RNA结合蛋白TDP - 43已被确定为额颞叶变性伴泛素化包涵体（FTLD - U）的标志性包涵体中存在的主要蛋白质，这表明转录失调在FTLD - U病理生理学中起作用。我们利用Affymetrix U133A微阵列平台，对人类FTLD - U大脑中组织病理学受影响和未受影响区域的全局基因表达进行了分析。然后，我们通过生物学通路分析、聚类和主成分分析以及基于大脑区域和颗粒蛋白前体（GRN）基因状态的亚组分析来描述差异基因表达。将17例FTLD - U大脑与11例对照进行比较，我们在额叶皮质中鉴定出414个上调基因和210个下调基因（P值<0.001）。此外，聚类和主成分分析显示，GRN基因有突变或可能存在致病性变异的样本（GRN +，17例中有7例）具有一种与正常对照以及缺乏GRN基因变异的FTLD - U样本（GRN -，17例中有10例）均不同的表达特征。在GRN + FTLD - U亚组中，我们在额叶皮质中发现了>1300个失调基因（P值<0.001），其中许多参与了在GRN +病例中独特失调的通路。我们的研究结果表明，GRN + FTLD - U具有独特的分子表型，在临床或组织病理学检查中不易察觉，这提示FTLD - U的GRN +和GRN -亚型具有不同的病理生理机制。此外，这些来自大量人类大脑的数据为未来疾病假说的检验提供了宝贵的资源。
Frontotemporal lobar degeneration is a fatal neurodegenerative disease that results in progressive decline in behavior, executive function and sometimes language. Disease mechanisms remain poorly understood. Recently, however, the DNA- and RNA-binding protein TDP-43 has been identified as the major protein present in the hallmark inclusion bodies of frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U), suggesting a role for transcriptional dysregulation in FTLD-U pathophysiology. Using the Affymetrix U133A microarray platform, we profiled global gene expression in both histopathologically affected and unaffected areas of human FTLD-U brains. We then characterized differential gene expression with biological pathway analyses, cluster and principal component analyses, and subgroup analyses based on brain region and progranulin (GRN) gene status. Comparing 17 FTLD-U brains to 11 controls, we identified 414 upregulated and 210 downregulated genes in frontal cortex (P-value < 0.001). Moreover, cluster and principal component analyses revealed that samples with mutations or possibly pathogenic variations in the GRN gene (GRN+, 7/17) had an expression signature that was distinct from both normal controls and FTLD-U samples lacking GRN gene variations (GRN-, 10/17). Within the subgroup of GRN+ FTLD-U, we found > 1300 dysregulated genes in frontal cortex (P-value < 0.001), many participating in pathways uniquely dysregulated in the GRN+ cases. Our findings demonstrate a distinct molecular phenotype for GRN+ FTLD-U, not readily apparent on clinical or histopathological examination, suggesting distinct pathophysiological mechanisms for GRN+ and GRN- subtypes of FTLD-U. In addition, these data from a large number of human brains provide a valuable resource for future testing of disease hypotheses.