RESUMEN
Cornelia de Lange syndrome (CdLS) is a dominantly inherited congenital malformation disorder, caused by mutations in the cohesin-loading protein NIPBL for nearly 60% of individuals with classical CdLS, and by mutations in the core cohesin components SMC1A (~5%) and SMC3 (<1%) for a smaller fraction of probands. In humans, the multisubunit complex cohesin is made up of SMC1, SMC3, RAD21 and a STAG protein. These form a ring structure that is proposed to encircle sister chromatids to mediate sister chromatid cohesion and also has key roles in gene regulation. SMC3 is acetylated during S-phase to establish cohesiveness of chromatin-loaded cohesin, and in yeast, the class I histone deacetylase Hos1 deacetylates SMC3 during anaphase. Here we identify HDAC8 as the vertebrate SMC3 deacetylase, as well as loss-of-function HDAC8 mutations in six CdLS probands. Loss of HDAC8 activity results in increased SMC3 acetylation and inefficient dissolution of the 'used' cohesin complex released from chromatin in both prophase and anaphase. SMC3 with retained acetylation is loaded onto chromatin, and chromatin immunoprecipitation sequencing analysis demonstrates decreased occupancy of cohesin localization sites that results in a consistent pattern of altered transcription seen in CdLS cell lines with either NIPBL or HDAC8 mutations.
Asunto(s)
Proteínas de Ciclo Celular/metabolismo , Proteínas Cromosómicas no Histona/metabolismo , Síndrome de Cornelia de Lange/genética , Síndrome de Cornelia de Lange/metabolismo , Histona Desacetilasas/genética , Mutación/genética , Proteínas Represoras/genética , Acetilación , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Anafase , Sitios de Unión , Proteínas de Ciclo Celular/química , Proteoglicanos Tipo Condroitín Sulfato/química , Proteoglicanos Tipo Condroitín Sulfato/metabolismo , Cromatina/genética , Cromatina/metabolismo , Inmunoprecipitación de Cromatina , Proteínas Cromosómicas no Histona/química , Cristalografía por Rayos X , Proteínas de Unión al ADN , Femenino , Fibroblastos , Células HeLa , Histona Desacetilasas/química , Histona Desacetilasas/deficiencia , Histona Desacetilasas/metabolismo , Humanos , Masculino , Modelos Moleculares , Proteínas Mutantes/química , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Proteínas Nucleares/metabolismo , Fosfoproteínas/metabolismo , Profase , Conformación Proteica , Proteínas/genética , Proteínas Represoras/química , Proteínas Represoras/deficiencia , Proteínas Represoras/metabolismo , Transcripción Genética , CohesinasRESUMEN
We prospectively investigated the relation of adaptation, timing of atrioventricular valve replacement (AVVR), valve type, size, durability of replacement valve, and preoperative cardiac function with prognosis of AVVR. The subjects included 26 patients[ 15.5 years old( day 2-43 years)] with functional single ventricle who underwent AVVR at our institution between August 1996 and January 2014. Of these patients, 24 had regurgitation, whereas 2 had stenosis. Of 7 patients who died, 3 were infants who died in the postoperative acute phase, and all of them had severe heart failure at the preoperative stage. The 5-year survival rate was 67% as assessed by Kaplan-Meier curve. On univariate analysis of the preoperative data, pulmonary artery pressure (PAP), pulmonary capillary wedge pressure, age at operation, body height, and body weight were significant risk factors for death;of these, only PAP remained in the last model for multiple regression analysis. AVVR for regurgitation is supposed to reduce cardiac volume load and help improve prognosis. Atrioventricular valve plasty or replacement should be performed prior to the development of severe heart failure.