RESUMEN
Mutations in the HDAC8 are considered to be a prominent cause of Cornelia de Lange syndrome 5, a leading cause of intellectual disability and social disability. Here, we report the generation of an induced pluripotent stem cell (iPSC) line from a 5-year-old girl diagnosed with autism spectrum disorder (ASD) who carries a heterozygous mutation in HDAC8 (c.1075C > T, p.Pro359Ser).
Asunto(s)
Trastorno del Espectro Autista , Síndrome de Cornelia de Lange , Células Madre Pluripotentes Inducidas , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/metabolismo , Preescolar , Síndrome de Cornelia de Lange/diagnóstico , Síndrome de Cornelia de Lange/genética , Síndrome de Cornelia de Lange/metabolismo , Femenino , Heterocigoto , Histona Desacetilasas/genética , Histona Desacetilasas/metabolismo , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Mutación/genética , Proteínas Represoras/genética , Proteínas Represoras/metabolismoRESUMEN
Purpose: Cornelia de Lange syndrome (CdLS) is a rare congenital developmental disorder, and cases caused by variants in SMC3 are infrequent. This article describes a case of CdLS related to a pathogenic variant in SMC3 and performs a literature review. Methods: We collected clinical data and biological samples from a 12-year-old boy with "short stature for 11 years". Gene variants in the proband were detected by whole-exome sequencing, and the variants in his parents were verified by Sanger sequencing. All SMC3-related CdLS patients from the PubMed and Web of Science databases were collected and summarized using the available data. Results: A pathogenic variant in SMC3 in the proband, c.1942A>G, was identified. Neither of his parents carried the same variant. Twenty-eight patients were diagnosed with CdLS with variants in SMC3, including the cases in this study and those reported in the literature, where half of the variant types were missense, followed by 32% (9/28) with a deletion and 11% (3/28) with a duplication. All patients showed symptoms of verbal development delay and intellectual disability to different degrees, and 90% patients had long eyelashes while 89% patients had arched eyebrows. Conclusion: This study summarized different gene variants in SMC3 and the frequencies of the various clinical manifestations according to the reported literature. For CdLS caused by SMC3 variants, short stature and facial dysmorphic features are the two most important clinical clues. Definite diagnosis of this rare disease may be challenging clinically; thus, it is significant to use molecular diagnosis.
Asunto(s)
Pueblo Asiatico/genética , Proteínas de Ciclo Celular/genética , Proteoglicanos Tipo Condroitín Sulfato/genética , Proteínas Cromosómicas no Histona/genética , Síndrome de Cornelia de Lange/patología , Mutación , Síndrome de Cornelia de Lange/etiología , Síndrome de Cornelia de Lange/metabolismo , Humanos , Masculino , Fenotipo , Pronóstico , Secuenciación del ExomaRESUMEN
Cohesin loader nipped-B-like protein (Nipbl) is increasingly recognized for its important role in development and cancer. Cornelia de Lange Syndrome (CdLS), mostly caused by heterozygous mutations of Nipbl, is an autosomal dominant disease characterized by multiorgan malformations. However, the regulatory role and underlying mechanism of Nipbl in skeletal development remain largely elusive. In this study, we constructed a Nipbl-a Cas9-knockout (KO) zebrafish, which displayed severe retardation of global growth and skeletal development. Deficiency of Nipbl remarkably compromised cell growth and survival, and osteogenic differentiation of mammalian osteoblast precursors. Furthermore, Nipbl depletion impaired the cell cycle process, and caused DNA damage accumulation and cellular senescence. In addition, nucleolar fibrillarin expression, global rRNA biogenesis, and protein translation were defective in the Nipbl-depleted osteoblast precursors. Interestingly, an integrated stress response inhibitor (ISRIB), partially rescued Nipbl depletion-induced cellular defects in proliferation and apoptosis, osteogenesis, and nucleolar function. Simultaneously, we performed transcriptome analysis of Nipbl deficiency on human neural crest cells and mouse embryonic fibroblasts in combination with Nipbl ChIP-Seq. We found that Nipbl deficiency caused thousands of differentially expressed genes including some important genes in bone and cartilage development. In conclusion, Nipbl deficiency compromised skeleton development through impairing osteoblast precursor cell proliferation and survival, and osteogenic differentiation, and also disturbing the expression of some osteogenesis-regulatory genes. Our study elucidated that Nipbl played a pivotal role in skeleton development, and supported the fact that treatment of ISRIB may provide an early intervention strategy to alleviate the bone dysplasia of CdLS.
Asunto(s)
Enfermedades del Desarrollo Óseo/genética , Síndrome de Cornelia de Lange/genética , Síndrome de Cornelia de Lange/metabolismo , Fibroblastos/metabolismo , Osteogénesis/genética , Animales , Enfermedades del Desarrollo Óseo/metabolismo , Segregación Cromosómica/genética , Heterocigoto , Mutación/genética , Fenotipo , Transcripción Genética/genética , Pez Cebra/genéticaRESUMEN
Precocious dissociation of sisters 5 (PDS5) is an associate protein of cohesin that is conserved from yeast to humans. It acts as a regulator of the cohesin complex and plays important roles in various cellular processes, such as sister chromatid cohesion, DNA damage repair, gene transcription, and DNA replication. Vertebrates have two paralogs of PDS5, PDS5A and PDS5B, which have redundant and unique roles in regulating cohesin functions. Herein, we discuss the molecular characteristics and functions of PDS5, as well as the effects of its mutations in the development of diseases and their relevance for novel therapeutic strategies.
Asunto(s)
Proteínas de Ciclo Celular/genética , Reparación del ADN , Proteínas de Unión al ADN/genética , Síndrome de Cornelia de Lange/genética , Neoplasias/genética , Proteínas Nucleares/genética , Proteínas de Saccharomyces cerevisiae/genética , Factores de Transcripción/genética , Animales , Proteínas de Ciclo Celular/química , Proteínas de Ciclo Celular/metabolismo , Secuencia Conservada , Daño del ADN , Replicación del ADN , Proteínas de Unión al ADN/química , Proteínas de Unión al ADN/metabolismo , Síndrome de Cornelia de Lange/metabolismo , Síndrome de Cornelia de Lange/patología , Expresión Génica , Humanos , Ratones , Ratones Noqueados , Modelos Moleculares , Neoplasias/metabolismo , Neoplasias/patología , Proteínas Nucleares/química , Proteínas Nucleares/metabolismo , Estructura Secundaria de Proteína , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/química , Proteínas de Saccharomyces cerevisiae/metabolismo , Intercambio de Cromátides Hermanas , Factores de Transcripción/química , Factores de Transcripción/metabolismoRESUMEN
Cornelia de Lange Syndrome (CdLS) is a human developmental disorder caused by mutations that compromise the function of cohesin, a major regulator of 3D genome organization. Cognitive impairment is a universal and as yet unexplained feature of CdLS. We characterize the transcriptional profile of cortical neurons from CdLS patients and find deregulation of hundreds of genes enriched for neuronal functions related to synaptic transmission, signalling processes, learning and behaviour. Inducible proteolytic cleavage of cohesin disrupts 3D genome organization and transcriptional control in post-mitotic cortical mouse neurons, demonstrating that cohesin is continuously required for neuronal gene expression. The genes affected by acute depletion of cohesin belong to similar gene ontology classes and show significant numerical overlap with genes deregulated in CdLS. Interestingly, reconstitution of cohesin function largely rescues altered gene expression, including the expression of genes deregulated in CdLS.
Asunto(s)
Proteínas de Ciclo Celular/genética , Proteínas Cromosómicas no Histona/genética , Síndrome de Cornelia de Lange/genética , Regulación de la Expresión Génica , Mutación , Neuronas/metabolismo , Adulto , Animales , Proteínas de Ciclo Celular/metabolismo , Células Cultivadas , Proteínas Cromosómicas no Histona/metabolismo , Síndrome de Cornelia de Lange/metabolismo , Perfilación de la Expresión Génica/métodos , Humanos , Ratones Endogámicos C57BL , Ratones Noqueados , Persona de Mediana Edad , Adulto Joven , CohesinasRESUMEN
Cornelia de Lange Syndrome (CdLS) is a rare genetic disorder, which causes a range of physical, cognitive, and medical challenges. To retrospectively analyze the clinical characteristics and genetic variations of Chinese patients, and to provide experience for further diagnosis and treatment of CdLS in Chinese children, we identified 15 unrelated Chinese children who presented with unusual facial features, short stature, developmental delay, limb abnormalities, and a wide range of health conditions. In this study, targeted-next generation sequencing was used to screen for causal variants and the clinically relevant variants were subsequently verified using Sanger sequencing. DNA sequencing identified 15 genetic variations, including 11 NIPBL gene variants, two SMC1A gene variants, one RAD21 gene variant, and one HDAC8 variant. The phenotype of these patients was summarized and differences between this cohort and another four groups were compared. The clinical manifestations of the patients in this cohort were mostly consistent with other ethnicities, but several clinical features in our cohort had different frequencies compared with other groups. We identified 15 deleterious variants of which 11 were novel. Variants in the NIPBL gene were the most common cause in our cohort. Our study not only expands upon the spectrum of genetic variations in CdLS, but also broadens our understanding of the clinical features of CdLS.
Asunto(s)
Proteínas de Ciclo Celular/genética , Síndrome de Cornelia de Lange/genética , Síndrome de Cornelia de Lange/fisiopatología , Anomalías Múltiples , Pueblo Asiatico , Niño , Preescolar , Proteínas Cromosómicas no Histona/genética , Estudios de Cohortes , Proteínas de Unión al ADN/genética , Síndrome de Cornelia de Lange/metabolismo , Femenino , Mutación del Sistema de Lectura , Genotipo , Heterocigoto , Secuenciación de Nucleótidos de Alto Rendimiento , Histona Desacetilasas/genética , Homocigoto , Humanos , Lactante , Masculino , Mutación Missense , Fenotipo , Empalme del ARN , Proteínas Represoras/genética , Estudios Retrospectivos , Eliminación de SecuenciaRESUMEN
Cohesin is an evolutionarily conserved chromosome-associated protein complex essential for chromosome segregation, gene expression, and repair of DNA damage. Mutations that affect this complex cause the human developmental disorder Cornelia de Lange syndrome (CdLS), thought to arise from defective embryonic transcription. We establish a significant role for placental defects in the development of CdLS mouse embryos (Nipbl and Hdac8). Placenta is a naturally senescent tissue; we demonstrate that persistent DNA damage potentiates senescence and activates cytokine signaling. Mutant embryo developmental outcomes are significantly improved in the context of a wild-type placenta or by genetically restricting cytokine signaling. Our study highlights that cohesin is required for maintaining ploidy and the repair of spontaneous DNA damage in placental cells, suggesting that genotoxic stress and ensuing placental senescence and cytokine production could represent a broad theme in embryo health and viability.
Asunto(s)
Daño del ADN/genética , Síndrome de Cornelia de Lange/genética , Expresión Génica/genética , Placenta/metabolismo , Animales , Segregación Cromosómica/genética , Síndrome de Cornelia de Lange/metabolismo , Femenino , Humanos , Ratones , Mutación/genética , Fenotipo , EmbarazoRESUMEN
Cornelia de Lange syndrome Spectrum (CdLSp) is characterized by intellectual disability, facial dysmorphisms, and growth impairment. Although eating difficulties are a well-known feature of the disease, there is no data regarding the nutritional deficiencies of these patients. The food intake was tracked using a dietary transcription provided by the family/caregivers, biochemical nutritional parameters were measured with laboratory tests and through an accurate clinical evaluation of the incidence of qualitative and quantitative imbalances in a cohort of 73 patients with CdLSp ware determined. Of these 73, 62 (85%) subjects provided a complete and detailed dietary transcription. In the studied population, a quantitative caloric imbalance in 47/62 (76%) subjects was observed. The caloric intake was low in 27/62 (43%) subjects whereas excessive in 20/62 (33%). Only 15/62 (24%) had an optimum caloric intake. Regarding micronutrients, a calcium intake deficiency in 32% of the patients (20/62) was observed. Blood tests revealed a low iron level in 22/73 (30%) of the patients and 25(OH)D deficiency in 49/73 (67%). Serum hypocalcemia was not evidenced. Qualitative and quantitative imbalances resulted in more frequent than expected in CdLSp patients. A qualitative imbalance was more prevalent in younger patients while in older patients prevailed mainly a quantitative disproportion. We found no statistically meaningful correlation between dietary imbalances, genetic, or clinical parameters. Our findings highlight the need for further studies to evaluate the basal metabolic rate of CdLSp patients and find a correlation with their growth impairment.
Asunto(s)
Síndrome de Cornelia de Lange/genética , Ingestión de Alimentos/genética , Discapacidad Intelectual/genética , Desnutrición/genética , Adolescente , Proteínas de Ciclo Celular/sangre , Niño , Preescolar , Proteínas Cromosómicas no Histona/sangre , Estudios de Cohortes , Síndrome de Cornelia de Lange/sangre , Síndrome de Cornelia de Lange/metabolismo , Síndrome de Cornelia de Lange/patología , Femenino , Humanos , Discapacidad Intelectual/sangre , Discapacidad Intelectual/metabolismo , Discapacidad Intelectual/patología , Hierro/sangre , Italia , Masculino , Desnutrición/sangre , Desnutrición/metabolismo , Desnutrición/patología , FenotipoRESUMEN
Mutations in NIPBL are the major cause of Cornelia de Lange Syndrome (CdLS). NIPBL is the cohesin-loading factor and has recently been associated with the BET (bromodomains and extra-terminal (ET) domain) proteins BRD2 and BRD4. Related to this, a CdLS-like phenotype has been described associated to BRD4 mutations. Here, we show direct interaction of NIPBL with different BET members in yeast, and selective interaction with BRD4 in cells, being the ET domain involved in the interaction. To understand the relationship between NIPBL and BET proteins, we have performed RNA-Seq expression analysis following depletion of the different proteins. Results indicate that genes regulated by NIPBL largely overlap with those regulated by BRD4 but not with those regulated by BRD2. ChIP-Seq analysis indicates preferential NIPBL occupancy at promoters, and knockdown experiments show mutual stabilization of NIPBL and BRD4 on co-regulated promoters. Moreover, human fibroblasts from CdLS probands with mutations in NIPBL show reduced BRD4 at co-occupied promoters. Functional analysis in vivo, using mutants of Drosophila melanogaster, confirmed the genetic interaction between Nipped-B and fs(1)h, the orthologs of human NIPBL and BRD4, respectively. Thus, we provide evidence for NIPBL and BRD4 cooperation in transcriptional regulation, which should contribute to explain the recently observed CdLS-like phenotype associated with BRD4 mutations.
Asunto(s)
Proteínas de Ciclo Celular/metabolismo , Síndrome de Cornelia de Lange/metabolismo , Drosophila melanogaster/metabolismo , Factores de Transcripción/metabolismo , Animales , Proteínas de Ciclo Celular/genética , Secuenciación de Inmunoprecipitación de Cromatina , Síndrome de Cornelia de Lange/genética , Drosophila melanogaster/genética , Fibroblastos/metabolismo , Regulación de la Expresión Génica/genética , Ontología de Genes , Células HEK293 , Humanos , Fenotipo , Regiones Promotoras Genéticas , Unión Proteica , Dominios Proteicos , RNA-Seq , Factores de Transcripción/genéticaRESUMEN
Cohesin is a conserved, ring-shaped protein complex that encircles sister chromatids and ensures correct chromosome segregation during mitosis and meiosis. It also plays a crucial role in the regulation of gene expression, DNA condensation, and DNA repair through both non-homologous end joining and homologous recombination. Cohesins are spatiotemporally regulated by the Scc2-Scc4 complex which facilitates cohesin loading onto chromatin at specific chromosomal sites. Over the last few years, much attention has been paid to cohesin and cohesin loader as it became clear that even minor disruptions of these complexes may lead to developmental disorders and cancers. Here we summarize recent developments in the structure of Scc2-Scc4 complex, cohesin loading process, and mediators that determine the Scc2-Scc4 binding patterns to chromatin.
Asunto(s)
Proteínas de Ciclo Celular/metabolismo , Proteínas Cromosómicas no Histona/metabolismo , Proteínas de Ciclo Celular/química , Cromátides/genética , Cromátides/metabolismo , Cromatina/genética , Cromatina/metabolismo , Ensamble y Desensamble de Cromatina , Proteínas Cromosómicas no Histona/química , Segregación Cromosómica , Síndrome de Cornelia de Lange/etiología , Síndrome de Cornelia de Lange/metabolismo , Susceptibilidad a Enfermedades , Humanos , Complejos Multiproteicos , Unión Proteica , Proteínas/genética , Proteínas/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Relación Estructura-Actividad , CohesinasRESUMEN
Cornelia de Lange Syndrome (CdLS) is a choesinopathy: a severe genetic disorder caused by mutations in the cohesin complex genes. The phenotype is characterized by typical facial dysmorphism, growth impairment and multiorgan abnormalities including brain alterations. Wnt pathway is known to play a fundamental role in central nervous system development and it has been shown that Wnt pathway is disrupted in CdLS animal models and patients cells. In this review we investigate the possible link between Wnt pathway disruption and brain abnormalities in Cornelia de Lange Syndrome as such molecular impairment could lead to an abnormal embryonic development resulting in brain abnormalities (i.e. microcephaly, cerebellar hypoplasia, abnormal cortical development) in patients with Cornelia de Lange Syndrome.
Asunto(s)
Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/metabolismo , Síndrome de Cornelia de Lange/diagnóstico , Síndrome de Cornelia de Lange/metabolismo , Vía de Señalización Wnt/fisiología , Encéfalo/anomalías , Encéfalo/patología , Disfunción Cognitiva/psicología , Síndrome de Cornelia de Lange/psicología , Humanos , Mutación/fisiologíaRESUMEN
BACKGROUND: Cornelia de Lange syndrome (CdLS) is a multisystem developmental disorder frequently associated with heterozygous loss-of-function mutations of Nipped-B-like (NIPBL), the human homolog of Drosophila Nipped-B. NIPBL loads cohesin onto chromatin. Cohesin mediates sister chromatid cohesion important for mitosis but is also increasingly recognized as a regulator of gene expression. In CdLS patient cells and animal models, expression changes of multiple genes with little or no sister chromatid cohesion defect suggests that disruption of gene regulation underlies this disorder. However, the effect of NIPBL haploinsufficiency on cohesin binding, and how this relates to the clinical presentation of CdLS, has not been fully investigated. Nipbl haploinsufficiency causes CdLS-like phenotype in mice. We examined genome-wide cohesin binding and its relationship to gene expression using mouse embryonic fibroblasts (MEFs) from Nipbl+/- mice that recapitulate the CdLS phenotype. RESULTS: We found a global decrease in cohesin binding, including at CCCTC-binding factor (CTCF) binding sites and repeat regions. Cohesin-bound genes were found to be enriched for histone H3 lysine 4 trimethylation (H3K4me3) at their promoters; were disproportionately downregulated in Nipbl mutant MEFs; and displayed evidence of reduced promoter-enhancer interaction. The results suggest that gene activation is the primary cohesin function sensitive to Nipbl reduction. Over 50% of significantly dysregulated transcripts in mutant MEFs come from cohesin target genes, including genes involved in adipogenesis that have been implicated in contributing to the CdLS phenotype. CONCLUSIONS: Decreased cohesin binding at the gene regions is directly linked to disease-specific expression changes. Taken together, our Nipbl haploinsufficiency model allows us to analyze the dosage effect of cohesin loading on CdLS development.
Asunto(s)
Proteínas de Ciclo Celular/metabolismo , Proteínas Cromosómicas no Histona/metabolismo , Síndrome de Cornelia de Lange/genética , Perfilación de la Expresión Génica/métodos , Haploinsuficiencia , Proteínas/genética , Animales , Sitios de Unión , Factor de Unión a CCCTC/química , Factor de Unión a CCCTC/genética , Factor de Unión a CCCTC/metabolismo , Metilación de ADN , Síndrome de Cornelia de Lange/metabolismo , Modelos Animales de Enfermedad , Expresión Génica , Regulación de la Expresión Génica , Estudio de Asociación del Genoma Completo , Humanos , Ratones , Regiones Promotoras Genéticas , Unión Proteica , Activación Transcripcional , CohesinasRESUMEN
BACKGROUND: Cornelia de Lange syndrome (CdLS) is a rare genetic disorder affecting the neurodevelopment, gastrointestinal, musculoskeletal systems. CdLS is caused by mutations within NIPBL, SMC1A, SMC3, RAD21, and HDAC8 genes. These genes codify for the "cohesin complex" playing a role in chromatid adhesion, DNA repair and gene expression regulation. The aim of this study was to investigate retinoic acid (RA) signaling pathway, a master developmental regulator, in CdLS cells. METHODS: Skin biopsies from CdLS patients and healthy controls were cultured and derived primary fibroblast cells were treated with RA or dimethyl sulfoxide (vehicle). After RA treatment, cells were harvested and RNA was isolated for quantitative real-time polymerase chain reaction experiments. RESULTS: We analyzed several components of RA metabolism in a human cell line of kidney fibroblasts (293T), in addition to fibroblasts collected from both NIPBL-mutated patients and healthy donors, with or without RA treatment. In all cases, ADH and RALDH1 gene expression was not affected by RA treatment, while CRABP1 was induced. CRABP2 was dramatically upregulated upon RA treatment in healthy donors but not in CdLS patients cells. CONCLUSION: We investigated if CdLS alterations are associated to perturbation of RA signaling. Cells derived from CdLS patients do not respond to RA signaling as efficiently as healthy controls. RA pathway alterations suggest a possible underlying mechanism for several cellular and developmental abnormalities associated with cohesin function. Birth Defects Research 109:1268-1276, 2017. © 2017 Wiley Periodicals, Inc.
Asunto(s)
Síndrome de Cornelia de Lange/genética , Síndrome de Cornelia de Lange/metabolismo , Tretinoina/metabolismo , Aldehído Deshidrogenasa/genética , Aldehído Deshidrogenasa/metabolismo , Familia de Aldehído Deshidrogenasa 1 , Proteínas de Ciclo Celular/genética , Línea Celular , Proteínas Cromosómicas no Histona/genética , Fibroblastos/metabolismo , Fibroblastos/patología , Expresión Génica , Genes cdc , Células HEK293 , Humanos , Mutación , Neurofisinas/genética , Neurofisinas/metabolismo , Precursores de Proteínas/genética , Precursores de Proteínas/metabolismo , Receptores de Ácido Retinoico/genética , Receptores de Ácido Retinoico/metabolismo , Retinal-Deshidrogenasa , Transducción de Señal , Piel/metabolismo , Piel/patología , Vasopresinas/genética , Vasopresinas/metabolismo , CohesinasRESUMEN
NIPBL, a cohesin loader, has been implicated in transcriptional control and genome organization. Mutations in NIPBL, cohesin, and its deacetylase HDAC8 result in Cornelia de Lange syndrome. We report activation of the RNA-sensing kinase PKR in human lymphoblastoid cell lines carrying NIPBL or HDAC8 mutations, but not SMC1A or SMC3 mutations. PKR activation can be triggered by unmodified RNAs. Gene expression profiles in NIPBL-deficient lymphoblastoid cells and mouse embryonic stem cells reveal lower expression of genes involved in RNA processing and modification. NIPBL mutant lymphoblastoid cells show reduced proliferation and protein synthesis with increased apoptosis, all of which are partially reversed by a PKR inhibitor. Non-coding RNAs from an NIPBL mutant line had less m(6)A modification and activated PKR activity in vitro. This study provides insight into the molecular pathology of Cornelia de Lange syndrome by establishing a relationship between NIPBL and HDAC8 mutations and PKR activation.
Asunto(s)
Síndrome de Cornelia de Lange/metabolismo , Mutación , Proteínas/metabolismo , ARN/biosíntesis , Factores de Transcripción/metabolismo , eIF-2 Quinasa/metabolismo , Animales , Proteínas de Ciclo Celular , Síndrome de Cornelia de Lange/genética , Activación Enzimática/genética , Histona Desacetilasas/genética , Histona Desacetilasas/metabolismo , Humanos , Ratones , Proteínas/genética , ARN/genética , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Factores de Transcripción/genética , eIF-2 Quinasa/genéticaRESUMEN
Genetic variants within components of the cohesin complex (NIPBL, SMC1A, SMC3, RAD21, PDS5, ESCO2, HDAC8) are believed to be responsible for a spectrum of human syndromes known as "cohesinopathies" that includes Cornelia de Lange Syndrome (CdLS). CdLS is a multiple malformation syndrome affecting almost any organ and causing severe developmental delay. Cohesinopathies seem to be caused by dysregulation of specific developmental pathways downstream of mutations in cohesin components. However, it is still unclear how mutations in different components of the cohesin complex affect the output of gene regulation. In this study, zebrafish embryos and SMC1A-mutated patient-derived fibroblasts were used to analyze abnormalities induced by SMC1A loss of function. We show that the knockdown of smc1a in zebrafish impairs neural development, increases apoptosis, and specifically down-regulates Ccnd1 levels. The same down-regulation of cohesin targets is observed in SMC1A-mutated patient fibroblasts. Previously, we have demonstrated that haploinsufficiency of NIPBL produces similar effects in zebrafish and in patients fibroblasts indicating a possible common feature for neurological defects and mental retardation in cohesinopathies. Interestingly, expression analysis of Smc1a and Nipbl in developing mouse embryos reveals a specific pattern in the hindbrain, suggesting a role for cohesins in neural development in vertebrates.
Asunto(s)
Apoptosis/fisiología , Proteínas de Ciclo Celular/metabolismo , Proteínas Cromosómicas no Histona/metabolismo , Ciclina D1/metabolismo , Síndrome de Cornelia de Lange/metabolismo , Factores de Transcripción/metabolismo , Pez Cebra/embriología , Animales , Apoptosis/genética , Proteínas de Ciclo Celular/genética , Proteínas Cromosómicas no Histona/genética , Síndrome de Cornelia de Lange/genética , Regulación hacia Abajo , Humanos , Ratones , Mutación/genética , Factores de Transcripción/genética , Pez Cebra/metabolismo , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismoRESUMEN
OBJECTIVE: The aim of this research was to present prenatal diagnosis of Langer-Giedion syndrome (LGS/TRPS type II) and Cornelia de Lange syndrome-4 (CDLS4). MATERIALS AND METHODS: A 36-year-old woman underwent amniocentesis at 17 weeks of gestation because of advanced maternal age. Conventional cytogenetic analysis of amniocentesis revealed an interstitial deletion of chromosome 8q or del(8)(q23.3q24.13). Level II prenatal ultrasound examination revealed craniofacial dysmorphism. The pregnancy was terminated, and a malformed fetus was delivered with characteristic craniofacial dysmorphism of LGS/TRPS type II and CDLS4. Whole-genome array comparative genomic hybridization (aCGH) on the DNA extracted from cultured amniocytes was performed. RESULTS: The analysis by aCGH revealed a result of arr 8q23.3q24.11 (116,087,006-118,969,399)×1, 8q24.13 (123,086,851-124,470,847)×1 (NCBI build 37) with a 2.88-Mb deletion of 8q23.3-q24.11 encompassing six OMIM genes, TRPS1, EIF3H, RAD21, SLC30A8, MED30, and EXT1, and a 1.383-Mb deletion of 8q24.13 encompassing four OMIM genes, ZHX2, DERL1, ZHX1, and ATAD2. CONCLUSION: In the present case, the conventional cytogenetic analysis of cultured amniocytes revealed del(8)(q23.3q24.13), whereas aCGH analysis of cultured amniocytes showed the deletions of 8q23.3-q24.11 and 8q24.13 with the presence of the segment 8q24.12. Therefore, aCGH provides the advantage of better understanding of the nature of interstitial deletion and genotype-phenotype correlation in this case.
Asunto(s)
Proteínas de Unión al ADN/genética , Síndrome de Cornelia de Lange/diagnóstico , Haploinsuficiencia/genética , Síndrome de Langer-Giedion/diagnóstico , N-Acetilglucosaminiltransferasas/genética , Proteínas Nucleares/genética , Fosfoproteínas/genética , Diagnóstico Prenatal/métodos , Factores de Transcripción/genética , Adulto , Amniocentesis , Proteínas de Ciclo Celular , Deleción Cromosómica , Cromosomas Humanos Par 8 , Hibridación Genómica Comparativa , ADN/análisis , Proteínas de Unión al ADN/metabolismo , Síndrome de Cornelia de Lange/genética , Síndrome de Cornelia de Lange/metabolismo , Diagnóstico Diferencial , Femenino , Humanos , Síndrome de Langer-Giedion/genética , Síndrome de Langer-Giedion/metabolismo , N-Acetilglucosaminiltransferasas/metabolismo , Proteínas Nucleares/metabolismo , Fosfoproteínas/metabolismo , Embarazo , Proteínas Represoras , Factores de Transcripción/metabolismoRESUMEN
Cornelia de Lange Syndrome (CdLS) is the most common example of disorders of the cohesin complex, or cohesinopathies. There are a myriad of clinical issues facing individuals with CdLS, particularly in the neurodevelopmental system, which also have implications for the parents and caretakers, involved professionals, therapists, and schools. Basic research in developmental and cell biology on cohesin is showing significant progress, with improved understanding of the mechanisms and the possibility of potential therapeutics. The following abstracts are presentations from the 6th Cornelia de Lange Syndrome Scientific and Educational Symposium, which took place on June 25-26, 2014, in conjunction with the Cornelia de Lange Syndrome Foundation National Meeting in Costa Mesa, CA. The Research Committee of the CdLS Foundation organizes the meeting, reviews and accepts abstracts, and subsequently disseminates the information to the families through members of the Clinical Advisory Board. In addition to the scientific and clinical discussions, there were educationally focused talks related to practical aspects of behavior and development. AMA CME credits were provided by Greater Baltimore Medical Center, Baltimore, MD.
Asunto(s)
Proteínas de Ciclo Celular/genética , Proteínas Cromosómicas no Histona/genética , Síndrome de Cornelia de Lange/genética , Regulación del Desarrollo de la Expresión Génica , Mutación , Adulto , Animales , California , Proteínas de Ciclo Celular/metabolismo , Niño , Proteínas Cromosómicas no Histona/metabolismo , Síndrome de Cornelia de Lange/metabolismo , Síndrome de Cornelia de Lange/patología , Modelos Animales de Enfermedad , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Humanos , Ratones , Fenotipo , Transducción de Señal , Pez Cebra/genética , Pez Cebra/metabolismo , CohesinasRESUMEN
Cohesin is a chromosome-associated protein complex that plays many important roles in chromosome function. Genetic screens in yeast originally identified cohesin as a key regulator of chromosome segregation. Subsequently, work by various groups has identified cohesin as critical for additional processes such as DNA damage repair, insulator function, gene regulation, and chromosome condensation. Mutations in the genes encoding cohesin and its accessory factors result in a group of developmental and intellectual impairment diseases termed 'cohesinopathies.' How mutations in cohesin genes cause disease is not well understood as precocious chromosome segregation is not a common feature in cells derived from patients with these syndromes. In this review, the latest findings concerning cohesin's function in the organization of chromosome structure and gene regulation are discussed. We propose that the cohesinopathies are caused by changes in gene expression that can negatively impact translation. The similarities and differences between cohesinopathies and ribosomopathies, diseases caused by defects in ribosome biogenesis, are discussed. The contribution of cohesin and its accessory proteins to gene expression programs that support translation suggests that cohesin provides a means of coupling chromosome structure with the translational output of cells.
Asunto(s)
Proteínas de Ciclo Celular/genética , Proteínas Cromosómicas no Histona/genética , Anomalías Craneofaciales/genética , Síndrome de Cornelia de Lange/genética , Ectromelia/genética , Hipertelorismo/genética , Animales , Proteínas de Ciclo Celular/metabolismo , Proteínas Cromosómicas no Histona/metabolismo , Anomalías Craneofaciales/etiología , Anomalías Craneofaciales/metabolismo , Síndrome de Cornelia de Lange/etiología , Síndrome de Cornelia de Lange/metabolismo , Ectromelia/etiología , Ectromelia/metabolismo , Humanos , Hipertelorismo/etiología , Hipertelorismo/metabolismo , Biosíntesis de Proteínas , CohesinasRESUMEN
Cornelia de Lange syndrome (CdLS) is a genetically heterogeneous disorder that presents with extensive phenotypic variability, including facial dysmorphism, developmental delay/intellectual disability (DD/ID), abnormal extremities, and hirsutism. About 65% of patients harbor mutations in genes that encode subunits or regulators of the cohesin complex, including NIPBL, SMC1A, SMC3, RAD21, and HDAC8. Wiedemann-Steiner syndrome (WDSTS), which shares CdLS phenotypic features, is caused by mutations in lysine-specific methyltransferase 2A (KMT2A). Here, we performed whole-exome sequencing (WES) of 2 male siblings clinically diagnosed with WDSTS; this revealed a hemizygous, missense mutation in SMC1A that was predicted to be deleterious. Extensive clinical evaluation and WES of 32 Turkish patients clinically diagnosed with CdLS revealed the presence of a de novo heterozygous nonsense KMT2A mutation in 1 patient without characteristic WDSTS features. We also identified de novo heterozygous mutations in SMC3 or SMC1A that affected RNA splicing in 2 independent patients with combined CdLS and WDSTS features. Furthermore, in families from 2 separate world populations segregating an autosomal-recessive disorder with CdLS-like features, we identified homozygous mutations in TAF6, which encodes a core transcriptional regulatory pathway component. Together, our data, along with recent transcriptome studies, suggest that CdLS and related phenotypes may be "transcriptomopathies" rather than cohesinopathies.
Asunto(s)
Codón sin Sentido , Síndrome de Cornelia de Lange , Exoma , Regulación de la Expresión Génica , Fenotipo , Transcriptoma , Adolescente , Adulto , Proteínas de Ciclo Celular/biosíntesis , Proteínas de Ciclo Celular/genética , Niño , Preescolar , Proteoglicanos Tipo Condroitín Sulfato/biosíntesis , Proteoglicanos Tipo Condroitín Sulfato/genética , Proteínas Cromosómicas no Histona/biosíntesis , Proteínas Cromosómicas no Histona/genética , Síndrome de Cornelia de Lange/genética , Síndrome de Cornelia de Lange/metabolismo , Síndrome de Cornelia de Lange/patología , Exonucleasas , Perfilación de la Expresión Génica , Estudio de Asociación del Genoma Completo , Heterocigoto , Histona Desacetilasas/biosíntesis , Histona Desacetilasas/genética , N-Metiltransferasa de Histona-Lisina , Humanos , Lactante , Masculino , Proteína de la Leucemia Mieloide-Linfoide/biosíntesis , Proteína de la Leucemia Mieloide-Linfoide/genética , Proteínas/genética , Proteínas/metabolismo , Proteínas Represoras/biosíntesis , Proteínas Represoras/genéticaRESUMEN
The cohesin complex is at the heart of many chromosomal activities, including sister chromatid cohesion and transcriptional regulation. Cohesin loading onto chromosomes depends on the Scc2-Scc4 cohesin loader complex, but the chromatin features that form cohesin loading sites remain poorly understood. Here we show that the RSC chromatin remodeling complex recruits budding yeast Scc2-Scc4 to broad nucleosome-free regions, which the cohesin loader helps to maintain. Consequently, inactivation of either the cohesin loader or the RSC complex has similar effects on nucleosome positioning, gene expression and sister chromatid cohesion. These results show an intimate link between local chromatin structure and higher-order chromosome architecture. Our findings pertain to the similarities between two severe human disorders, Cornelia de Lange syndrome, which is caused by alterations in the human cohesin loader, and Coffin-Siris syndrome, which results from alterations in human RSC complex components. Both syndromes can arise from gene misregulation due to related changes in the nucleosome landscape.