title: Proteomic profile identifies dysregulated pathways in Cornelia de Lange syndrome cells with distinct mutations in SMC1A and SMC3 genes.
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.
authors.affiliation: Functional Proteomics Laboratory, Department of Biotechnologies, University of Siena, Siena, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Gimigliano
authors.forename: Linda
authors.initials: L
authors.lastname: Mannini
authors.forename: Laura
authors.initials: L
authors.lastname: Bianchi
authors.forename: Michele
authors.initials: M
authors.lastname: Puglia
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Deardorff
authors.forename: Stefania
authors.initials: S
authors.lastname: Menga
authors.forename: Ian D
authors.initials: ID
authors.lastname: Krantz
authors.forename: Antonio
authors.initials: A
authors.lastname: Musio
authors.forename: Luca
authors.initials: L
authors.lastname: Bini
mesh_terms: D000595:Amino Acid Sequence; D016022:Case-Control Studies; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D011508:Chondroitin Sulfate Proteoglycans / Q000235:genetics / Q000378:metabolism*; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins; D003635:De Lange Syndrome / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D042822:Genomic Instability; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress; D010641:Phenotype; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D061251:Primary Cell Culture; D060066:Protein Interaction Maps; D017434:Protein Structure, Tertiary; D020543:Proteome / Q000032:analysis* / Q000378:metabolism; D040901:Proteomics / Q000379:methods; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D057825:Two-Dimensional Difference Gel Electrophoresis; D000098550:Structural Maintenance of Chromosome Protein 1
chemical_list: D018797:Cell Cycle Proteins; D011508:Chondroitin Sulfate Proteoglycans; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; C489427:MYC protein, human; D009687:Nuclear Proteins; D010750:Phosphoproteins; D020543:Proteome; D016271:Proto-Oncogene Proteins c-myc; C429022:RAD21 protein, human; C492318:SMC3 protein, human; D000098550:Structural Maintenance of Chromosome Protein 1