小胖威利综合征和天使综合征细胞株培养液的代谢组学差异分析
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摘要
小胖威利综合征和天使综合征是两种在15号染色体长臂(15q11-q13)发生基因变异的遗传性疾病。本研究对这两种细胞株的培养液开展基于高效液相色谱-质谱联用的代谢物组学数据收集,并利用XCMS在线分析平台对代谢产物组进行全局对比分析。通过Metlin数据库筛查代谢物组差异分析所命中的代谢产物,进一步依据Bio Cyc Pathway数据库绘制出包含这些显著差异代谢物结点的代谢网络通路。数据分析共发现了70种显著差异的代谢物和36个被高度覆盖的代谢通路,在此基础上探究了首次发现的、在代谢差异分析中最为显著的吗啡生物合成和尼古丁降解通路与疾病表型的潜在关联性,为遗传疾病的无损分子诊断提供了代谢组学基础和生物标志物候选靶标。
Prader-Willi and Angelman syndromes are two genetic diseases caused by mutations on the long arm of chromosome 15(15q11-q13). We carried out LCMS data collection on the culture solutions of the two disease cell strains, and then studied their metabolomics differentiation with online XCMS tool. The global metabolomics analysis gave the 70 most significant metabolites using Metlin database, resulting in the 36 top related pathways based on Bio Cyc Pathway database. We analyzed the most significant pathways, including morphine biosynthesis and nicotine degradation pathways at the genetic and metabolic levels. These outcomes may provide fundamental understandings and biomarker candidates on the two diseases in a viewpoint of metabolomics.
Prader-Willi and Angelman syndromes are two genetic diseases caused by mutations on the long arm of chromosome 15(15q11-q13). We carried out LCMS data collection on the culture solutions of the two disease cell strains, and then studied their metabolomics differentiation with online XCMS tool. The global metabolomics analysis gave the 70 most significant metabolites using Metlin database, resulting in the 36 top related pathways based on Bio Cyc Pathway database. We analyzed the most significant pathways, including morphine biosynthesis and nicotine degradation pathways at the genetic and metabolic levels. These outcomes may provide fundamental understandings and biomarker candidates on the two diseases in a viewpoint of metabolomics.
引文
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[10]David C,Perry M I.Dávila-García,Craig A.Stockmeier,et al.Increased nicotinic receptors in brains from smokers:membrane binding and autoradiography studies[J].JPharmacol Exp Ther,1999,289(3):1545-1552.
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[12]Thorfinn T,Riday E C.Dankoski M C K,et al.Pathwayspecific dopaminergic deficits in a mouse model of Angelman syndrome[J].J Clin Invest,2012,122(12):4544-4554.
[13]Danielle B,Megan C,Nancy M P.Obesity and Its Relationship to Addictions:Is Overeating a Form of Addictive Behavior[J].Am J Addict,2009,18(6):439-451.
[2]Yonatan S,Ido S,Ofra Y,et al.The noncoding RNAIPW regulates the imprinted DLK1-DIO3 locus in an induced pluripotent stem cell model of Prader-Willi syndrome[J].Nat Genet,2014,46(6):551-557.
[3]Douglas C.Bittel N K,Zohreh T,et al.Microarray analysis of gene/transcript expression in Angelman syndrome:deletion versus UPD[J].Genomics,2005,85(1):85-91.
[4]Ralf T,Gary J.Patti D R,et al.XCMS Online:A WebBased Platform to Process Untargeted Metabolomic Data[J].Analytical Chemistry,2012,84(11):5035-5039.
[5]Shuzhao L,Youngja P,Sai D,et al.Predicting network activity from high throughput metabolomics[J].PLo S Comput Biol,2013,9(7):e1003123.
[6]Patti G J,Tautenhahn R,Rinehart D,et al.A View from Above:The Cloud Plot for Visualizing Global Metabolomic Data[J].Analytical Chemistry,2013,85(2):798-804.
[7]Tautenhahn R,Cho K Y,Uritboonthai W,et al.An accelerated workflow for untargeted metabolomics using the METLIN database[J].Nature Biotechnology,2012,30(9):826-828.
[8]Soo J K,Jennifer L,Miller P J K,et al.Unique and atypical deletions in Prader-Willi syndrome reveal distinct phenotypes[J].Eur J Hum Genet,2012,20(3):283-290.
[9]Chotima B,Monika F,Christian B,et al.How human neuroblastoma cells make morphine.PNAS,2005,102(24):8495-8500.
[10]David C,Perry M I.Dávila-García,Craig A.Stockmeier,et al.Increased nicotinic receptors in brains from smokers:membrane binding and autoradiography studies[J].JPharmacol Exp Ther,1999,289(3):1545-1552.
[11]Luck C,Vitaterna M H,Wevrick R.Dopamine pathway imbalance in mice lacking Magel2,a Prader-Willi syndrome candidate gene[J].Behavioral Neuroscience,2016,130(4):448-459.
[12]Thorfinn T,Riday E C.Dankoski M C K,et al.Pathwayspecific dopaminergic deficits in a mouse model of Angelman syndrome[J].J Clin Invest,2012,122(12):4544-4554.
[13]Danielle B,Megan C,Nancy M P.Obesity and Its Relationship to Addictions:Is Overeating a Form of Addictive Behavior[J].Am J Addict,2009,18(6):439-451.