Proteomic profile identifies dysregulated pathways in Cornelia de Lange syndrome cells with distinct mutations in SMC1A and SMC3 genes.
Proteomic profile identifies dysregulated pathways in Cornelia de Lange syndrome cells with distinct mutations in SMC1A and SMC3 genes.
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DOI：
10.1021/pr300760p
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发表时间：
2012-12-07
影响因子：
4.4
通讯作者：
Bini L
中科院分区：
文献类型：
--
作者：
Gimigliano A;Mannini L;Bianchi L;Puglia M;Deardorff MA;Menga S;Krantz ID;Musio A;Bini L
在科尔内利亚德兰格综合征（CdLS）中已经发现了粘连蛋白基因的突变，但其发病机制仍然知之甚少。为了定义在CdLS中受影响的生化途径，我们分析了在核心粘附素基因SMC 1A和SMC 3中携带突变的CdLS细胞系的蛋白质组学谱。与对照组相比，在CdLS先证者中发现了失调的蛋白质表达。蛋白质组学分析能够区分在SMC蛋白质的不同结构域中携带突变的先证者。特别是，参与氧化应激反应的蛋白质在铰链突变的先证者中特异性下调。此外，CdLS细胞系显示出整体氧化应激增加的发现表明，它可能有助于一些CdLS表型特征，如过早的生理老化和基因组不稳定性。最后，c-MYC基因代表位于失调途径中心的会聚枢纽，并且在CdLS中下调。这项研究使我们能够突出，第一次，在CdLS中受到影响的特定生化途径，为CdLS中看到的一些表型特征提供了合理的因果证据。
Mutations in cohesin genes have been identified in Cornelia de Lange syndrome (CdLS), but its etiopathogenetic mechanisms are still poorly understood. To define biochemical pathways that are affected in CdLS we analyzed the proteomic profile of CdLS cell lines carrying mutations in the core cohesin genes, SMC1A and SMC3. Dysregulated protein expression was found in CdLS probands compared to controls. The proteomics analysis was able to discriminate between probands harboring mutations in the different domains of the SMC proteins. In particular, proteins involved in the response to oxidative stress were specifically down-regulated in hinge mutated probands. In addition, the finding that CdLS cell lines show an increase in global oxidative stress argues that it could contribute to some CdLS phenotypic features such as premature physiological aging and genome instability. Finally, the c-MYC gene represents a convergent hub lying at the center of dysregulated pathways, and is down-regulated in CdLS. This study allowed us to highlight, for the first time, specific biochemical pathways that are affected in CdLS, providing plausible causal evidence for some of the phenotypic features seen in CdLS.
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影响因子：
7
作者：
Karp, Natasha A.;McCormick, Paul S.;Lilley, Kathryn S.
通讯作者：
Lilley, Kathryn S.
影响因子：
16
作者：
Haering, CH;Löwe, J;Nasmyth, K
通讯作者：
Nasmyth, K
影响因子：
2.9
作者：
BJELLQVIST, B;HUGHES, GJ;HOCHSTRASSER, D
通讯作者：
HOCHSTRASSER, D
影响因子：
16
作者：
Haering, CH;Schoffnegger, D;Löwe, J
通讯作者：
Löwe, J
影响因子：
4.6
作者：
Dorsett, D;Eissenberg, JC;McKim, K
通讯作者：
McKim, K