RESUMEN
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.
Asunto(s)
Proteínas de Ciclo Celular/metabolismo , Proteoglicanos Tipo Condroitín Sulfato/metabolismo , Proteínas Cromosómicas no Histona/metabolismo , Síndrome de Cornelia de Lange/metabolismo , Mutación , Proteoma/análisis , Secuencia de Aminoácidos , Estudios de Casos y Controles , Proteínas de Ciclo Celular/genética , Proteoglicanos Tipo Condroitín Sulfato/genética , Proteínas Cromosómicas no Histona/genética , Proteínas de Unión al ADN , Síndrome de Cornelia de Lange/patología , Femenino , Regulación de la Expresión Génica , Inestabilidad Genómica , Humanos , Masculino , Espectrometría de Masas , Datos de Secuencia Molecular , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Estrés Oxidativo , Fenotipo , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Cultivo Primario de Células , Mapas de Interacción de Proteínas , Estructura Terciaria de Proteína , Proteoma/metabolismo , Proteómica/métodos , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Transcripción Genética , Electroforesis Bidimensional Diferencial en GelRESUMEN
Cornelia de Lange syndrome is a pleiotropic developmental syndrome characterized by growth and cognitive impairment, facial dysmorphic features, limb anomalies, and other malformations. Mutations in core cohesin genes SMC1A and SMC3, and the cohesin regulatory gene, NIPBL, have been identified in Cornelia de Lange syndrome probands. Patients with NIPBL mutations have more severe phenotypes when compared to those with mutations in SMC1A or SMC3. To date, 26 distinct SMC1A mutations have been identified in patients with Cornelia de Lange syndrome. Here, we describe a 3-year-old girl with psychomotor and cognitive impairment, mild facial dysmorphic features but no limb anomaly, heterozygous for a c.1487G>A mutation in SMC1A which predicts p.Arg496His. We show that this mutation leads to an impairment of the cellular response to genotoxic treatments.
Asunto(s)
Proteínas de Ciclo Celular/genética , Proteínas Cromosómicas no Histona/genética , Daño del ADN , Síndrome de Cornelia de Lange/genética , Línea Celular , Preescolar , Codón , Femenino , Heterocigoto , Humanos , Mutación , CohesinasRESUMEN
Cohesin is responsible for sister chromatid cohesion, ensuring the correct chromosome segregation. Beyond this role, cohesin and regulatory cohesin genes seem to play a role in preserving genome stability and gene transcription regulation. DNA damage is thought to be a major culprit for many human diseases, including cancer. Our present knowledge of the molecular basis underlying genome instability is extremely limited. Mutations in cohesin genes cause human diseases such as Cornelia de Lange syndrome and Roberts syndrome/SC phocomelia, and all the cell lines derived from affected patients show genome instability. Cohesin mutations have also been identified in colorectal cancer. Here, we will discuss the human disorders caused by alterations of cohesin function, with emphasis on the emerging role of cohesin as a genome stability caretaker.