Proteomic profile identifies dysregulated pathways in Cornelia de Lange syndrome cells with distinct mutations in
Anna Gimigliano1, Linda Mannini, Laura Bianchi
1Functional Proteomics Laboratory, Department of Biotechnologies, University of Siena, Siena, Italy.
Abstract:
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.
Insights
Cornelia de Lange syndrome (CdLS) involves cohesin gene mutations. This study reveals altered protein expression and increased oxidative stress, implicating c-MYC dysregulation in CdLS pathogenesis and features like aging and genome instability.
Area of Science:
- Genetics
- Molecular Biology
- Biochemistry
Background:
- Cornelia de Lange syndrome (CdLS) is linked to mutations in cohesin genes, but its underlying mechanisms remain unclear.
- Understanding these mechanisms is crucial for identifying potential therapeutic targets.
Purpose of the Study:
- To investigate the proteomic profile of CdLS cell lines with mutations in SMC1A and SMC3 core cohesin genes.
- To identify specific biochemical pathways affected in CdLS and their contribution to disease phenotypes.
Main Methods:
- Proteomic profiling of CdLS cell lines compared to control lines.
- Analysis of protein expression differences, focusing on pathways related to oxidative stress.
- Investigation of the role of the c-MYC gene in CdLS.
Main Results:
- CdLS cell lines exhibited dysregulated protein expression compared to controls.
- Proteomics successfully differentiated between mutations in different SMC protein domains.
- Proteins involved in oxidative stress response were down-regulated in hinge-mutated CdLS, with increased global oxidative stress observed.
- The c-MYC gene was found to be down-regulated, acting as a central hub in affected pathways.
Conclusions:
- This study identifies specific biochemical pathways disrupted in CdLS, offering insights into disease etiology.
- Increased oxidative stress and c-MYC down-regulation are implicated in CdLS phenotypes, including premature aging and genome instability.
