Finch NiCole A, Wang Xue, Baker Matthew C, Heckman Michael G, Gendron Tania F, Bieniek Kevin F, Wuu Joanne, DeJesus-Hernandez Mariely, Brown Patricia H, Chew Jeannie, Jansen-West Karen R, Daughrity Lillian M, Nicholson Alexandra M, Murray Melissa E, Josephs Keith A, Parisi Joseph E, Knopman David S, Petersen Ronald C, Petrucelli Leonard, Boeve Bradley F, Graff-Radford Neill R, Asmann Yan W, Dickson Dennis W, Benatar Michael, Bowser Robert, Boylan Kevin B, Rademakers Rosa, van Blitterswijk Marka
Department of Neuroscience (N.A.F., M.C.B., T.F.G., K.F.B., M.D.-H., P.H.B., J.C., K.R.J.-W., L.M.D., A.M.N., M.E.M., L.P., D.W.D., R.R., M.v.B.), Department of Health Sciences Research (X.W., Y.W.A.), Department of Neurology (N.R.G.-R., K.B.B.), Division of Biomedical Statistics and Informatics (M.G.H.), Mayo Clinic, Jacksonville, FL; Department of Neurology (J.W., M.B.), University of Miami, FL; Department of Neurology (K.A.J., J.E.P., D.S.K., R.C.P., B.F.B.), Mayo Clinic, Rochester, MN; and Divisions of Neurology and Neurobiology (R.B.), Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ.
Neurol Genet. 2017 Jun 7;3(4):e161. doi: 10.1212/NXG.0000000000000161. eCollection 2017 Aug.
We performed a genome-wide brain expression study to reveal the underpinnings of diseases linked to a repeat expansion in chromosome 9 open reading frame 72 ().
The genome-wide expression profile was investigated in brain tissue obtained from expansion carriers (n = 32), patients without this expansion (n = 30), and controls (n = 20). Using quantitative real-time PCR, findings were confirmed in our entire pathologic cohort of expansion carriers (n = 56) as well as nonexpansion carriers (n = 31) and controls (n = 20).
Our findings were most profound in the cerebellum, where we identified 40 differentially expressed genes, when comparing expansion carriers to patients without this expansion, including 22 genes that have a homeobox (e.g., genes) and/or are located within the gene cluster (top hit: homeobox A5 []). In addition to the upregulation of multiple homeobox genes that play a vital role in neuronal development, we noticed an upregulation of transthyretin (), an extracellular protein that is thought to be involved in neuroprotection. Pathway analysis aligned with these findings and revealed enrichment for gene ontology processes involved in (anatomic) development (e.g., organ morphogenesis). Additional analyses uncovered that and levels are associated with variant 2 levels as well as with intron-containing transcript levels, and thus, disease-related changes in those transcripts may have triggered the upregulation of and .
In conclusion, our identification of genes involved in developmental processes and neuroprotection sheds light on potential compensatory mechanisms influencing the occurrence, presentation, and/or progression of -related diseases.
我们进行了一项全基因组脑表达研究，以揭示与9号染色体开放阅读框72（）中重复扩增相关疾病的潜在机制。
对来自重复扩增携带者（n = 32）、无此扩增的患者（n = 30）和对照组（n = 20）的脑组织进行全基因组表达谱研究。使用定量实时PCR，在我们整个重复扩增携带者病理队列（n = 56）、无扩增携带者（n = 31）和对照组（n = 20）中对结果进行了验证。
我们的发现以小脑最为显著，在比较重复扩增携带者与无此扩增的患者时，我们鉴定出40个差异表达基因，其中包括22个具有同源框的基因（例如基因）和/或位于基因簇内的基因（最显著的是同源框A5 []）。除了多个在神经元发育中起关键作用的同源框基因上调外，我们还注意到转甲状腺素（）上调，这是一种被认为参与神经保护的细胞外蛋白。通路分析与这些发现一致，并揭示了参与（解剖学）发育（如器官形态发生）的基因本体过程的富集。进一步分析发现，和水平与变体2水平以及含内含子转录本水平相关，因此，这些转录本中与疾病相关的变化可能触发了和的上调。
总之，我们对参与发育过程和神经保护的基因的鉴定揭示了影响相关疾病发生、表现和/或进展的潜在补偿机制。
