RESUMEN
PURPOSE: Crohn's disease is a chronic gastrointestinal inflammatory disease with possible extraintestinal symptoms. There are predisposing genetic factors and even monogenic variants of the disorder. One of the possible genetic factors are variants of the DUOX2 gene. The protein product of the DUOX2 gene is a dual oxidase enzyme producing H2O2 in the bowel. Reduced H2O2 levels impact mucosal homeostasis and contribute to the development of inflammatory bowel disease. Thus far, only 19 patients with IBD with the DUOX2 variants have been described. METHODS: Here we present a case report of an adolescent female diagnosed at eleven years of age with IBD that was subsequently reclassified as Crohn's disease. She was treated with immunosuppressants and biological therapy but experienced additional complications. Her peripheral blood lymphocyte DNA was studied using massive parallel sequencing. Detected variants were functionally studied. RESULTS: Whole exome sequencing found two novel DUOX2 gene variants: a de novo variant c.3646C>T; p.R1216W and a maternally inherited variant c.3391G>A; p.A1131T which were initially classified as variants of unknown significance. However, follow-up functional studies demonstrated that both DUOX2 variants led to impaired H2O2 generation, which led to their reclassification to the likely pathogenic class according to the ACMG.net. Therefore, we conclude that these variants are causative for the disease. CONCLUSIONS: Identifying novel variants in patients with Crohn's disease and their families is important for precision medicine approaches and understanding of the pathogenesis of likely "monogenic" rare forms of inflammatory bowel disease.
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Enfermedad de Crohn , Enfermedades Inflamatorias del Intestino , Humanos , Adolescente , Femenino , Enfermedad de Crohn/genética , Oxidasas Duales/genética , Peróxido de Hidrógeno , Enfermedades Inflamatorias del Intestino/genéticaRESUMEN
The influence of aging on intestinal stem cells and their niche can explain underlying causes for perturbation in their function observed during aging. Molecular mechanisms for such a decrease in the functionality of intestinal stem cells during aging remain largely undetermined. Using transcriptome-wide approaches, our study demonstrates that aging intestinal stem cells strongly upregulate antigen presenting pathway genes and over-express secretory lineage marker genes resulting in lineage skewed differentiation into the secretory lineage and strong upregulation of MHC class II antigens in the aged intestinal epithelium. Mechanistically, we identified an increase in proinflammatory cells in the lamina propria as the main source of elevated interferon gamma (IFNγ) in the aged intestine, that leads to the induction of Stat1 activity in intestinal stem cells thus priming the aberrant differentiation and elevated antigen presentation in epithelial cells. Of note, systemic inhibition of IFNγ-signaling completely reverses these aging phenotypes and reinstalls regenerative capacity of the aged intestinal epithelium.
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Interferón gamma , Intestinos , Homeostasis , Interferón gamma/metabolismo , Mucosa Intestinal , Intestinos/metabolismo , Animales , Ratones , Factor de Transcripción STAT1/metabolismoRESUMEN
BACKGROUND: Schimke immunoosseous dysplasia (SIOD) is an ultra-rare inherited disease affecting many organ systems. Spondyloepiphyseal dysplasia, T-cell immunodeficiency and steroid resistant nephrotic syndrome are the main symptoms of this disease. CASE PRESENTATION: We aimed to characterize the clinical, pathological and genetic features of SIOD patients received at tertiary Pediatric Nephrology Center, University Hospital Motol, Prague, Czech Republic during the period 2001-2021. The mean age at diagnosis was 21 months (range 18-48 months). All patients presented with growth failure, nephropathy and immunodeficiency. Infections and neurologic complications were present in most of the affected children during the course of the disease. CONCLUSIONS: Although SIOD is a disease characterized by specific features, the individual phenotype may differ. Neurologic signs can severely affect the quality of life; the view on the management of SIOD is not uniform. Currently, new therapeutic methods are required.
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Síndromes de Inmunodeficiencia , Síndrome Nefrótico , Osteocondrodisplasias , Humanos , Síndrome Nefrótico/diagnóstico , Síndrome Nefrótico/genética , Síndrome Nefrótico/complicaciones , Osteocondrodisplasias/diagnóstico , Osteocondrodisplasias/genética , Osteocondrodisplasias/terapia , Centros de Atención Terciaria , República Checa , Calidad de Vida , Enfermedades Raras , Síndromes de Inmunodeficiencia/diagnóstico , Síndromes de Inmunodeficiencia/genética , Síndromes de Inmunodeficiencia/complicacionesRESUMEN
The correct establishment of DNA methylation patterns during mouse early development is essential for cell fate specification. However, the molecular targets as well as the mechanisms that determine the specificity of the de novo methylation machinery during differentiation are not completely elucidated. Here we show that the DNMT3B-dependent DNA methylation of key developmental regulatory regions at epiblast-like cells (EpiLCs) provides an epigenetic priming that ensures flawless commitment at later stages. Using in vitro stem cell differentiation and loss of function experiments combined with high-throughput genome-wide bisulfite-, bulk-, and single cell RNA-sequencing we dissected the specific role of DNMT3B in cell fate. We identify DNMT3B-dependent regulatory elements on the genome which, in Dnmt3b knockout (3BKO), impair the differentiation into meso-endodermal (ME) progenitors and redirect EpiLCs towards the neuro-ectodermal lineages. Moreover, ectopic expression of DNMT3B in 3BKO re-establishes the DNA methylation of the master regulator Sox2 super-enhancer, downmodulates its expression, and restores the expression of ME markers. Taken together, our data reveal that DNMT3B-dependent methylation at the epiblast stage is essential for the priming of the meso-endodermal lineages and provide functional characterization of the de novo DNMTs during EpiLCs lineage determination.
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Endodermo , Células Madre Embrionarias de Ratones , Animales , Ratones , Células Madre Embrionarias de Ratones/metabolismo , Endodermo/metabolismo , ADN (Citosina-5-)-Metiltransferasas/genética , Diferenciación Celular , Linaje de la Célula , Metilación de ADNRESUMEN
Calorie restriction has been recently shown to increase intestinal stem cell competition and to reduce mutation fixation in young mice. However, the impact of aging on this process is unknown. By employing Confetti reporter mice, here we show that, unexpectedly, old mice have more intestinal stem cell (ISC) competition than young mice. Moreover, differently from what observed in young mice, calorie restriction, when applied at late-life, decreases this process. Importantly, we also observed a strong correlation between the ISC competition and Paneth cell number. In vivo analysis and in vitro organoid experiments indicated that Paneth cells play a major role in driving intestinal stem cell competition and crypt clonality. Taken together, our results provide evidence that increasing the number of Paneth cells can increase the number of competitive ISCs, representing a valuable therapeutic target to delay fixation of mutated intestinal stem cells.
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Restricción Calórica , Células de Paneth , Ratones , Animales , Competencia Celular , Intestinos , Células Madre , Mucosa IntestinalRESUMEN
BACKGROUND: Patients with colon adenocarcinoma (COAD) exhibit significant heterogeneity in overall survival. The current tumor-node-metastasis staging system is insufficient to provide a precise prediction for prognosis. Identification and evaluation of new risk models by using big cancer data may provide a good way to identify prognosis-related signature. METHODS: We integrated different datasets and applied bioinformatic and statistical methods to construct a robust immune-associated risk model for COAD prognosis. Furthermore, a nomogram was constructed based on the gene signature and clinicopathological features to improve risk stratification and quantify risk assessment for individual patients. RESULTS: The immune-associated risk model discriminated high-risk patients in our investigated and validated cohorts. Survival analyses demonstrated that our gene signature served as an independent risk factor for overall survival and the nomogram exhibited high accuracy. Functional analysis interpreted the correlation between our risk model and its role in prognosis by classifying groups with different immune activities. Remarkably, patients in the low-risk group showed higher immune activity, while those in the high-risk group displayed a lower immune activity. CONCLUSIONS: Our study provides a novel tool that may contribute to the optimization of risk stratification for survival and personalized management of COAD.
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Adenocarcinoma , Neoplasias del Colon , Adenocarcinoma/patología , Neoplasias del Colon/genética , Humanos , Nomogramas , Pronóstico , Factores de RiesgoRESUMEN
Aging is characterized by a chronic low-grade inflammation known as inflammaging in multiple tissues, representing a risk factor for age-related diseases. Dietary restriction (DR) is the best-known non-invasive method to ameliorate aging in many organisms. However, the molecular mechanism and the signaling pathways that drive inflammaging across different tissues and how they are modulated by DR are not yet understood. Here we identify a multi-tissue gene network regulating inflammaging. This network is characterized by chromatin opening and upregulation in the transcription of innate immune system receptors and by activation of interferon signaling through interferon regulatory factors, inflammatory cytokines, and Stat1-mediated transcription. DR ameliorates aging-induced alterations of chromatin accessibility and RNA transcription of the inflammaging gene network while failing to rescue those alterations on the rest of the genome. Our results present a comprehensive understanding of the molecular network regulating inflammation in aging and DR and provide anti-inflammaging therapeutic targets.
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Envejecimiento , Inflamación , Envejecimiento/fisiología , Cromatina , Humanos , Inmunidad Innata , Inflamación/metabolismo , Interferones/metabolismo , Receptores Inmunológicos/metabolismo , Regulación hacia ArribaRESUMEN
We performed massive single-cell sequencing in the aging mouse colonic epithelium and immune cells. We identified novel compartment-specific markers as well as dramatic aging-associated changes in cell composition and signaling pathways, including a shift from absorptive to secretory epithelial cells, depletion of naive lymphocytes, and induction of eIF2 signaling. Colon cancer is one of the leading causes of death within the western world, incidence of which increases with age. The colonic epithelium is a rapidly renewing tissue, tasked with water and nutrient absorption, as well as hosting intestinal microbes. The colonic submucosa is populated with immune cells interacting with and regulating the epithelial cells. However, it is unknown whether compartment-specific changes occur during aging and what impact this would cause. We show that both epithelial and immune cells differ significantly between colonic compartments and experience significant age-related changes in mice. We found a shift in the absorptive-secretory cell balance, possibly linked to age-associated intestinal disturbances, such as malabsorption. We demonstrate marked changes in aging immune cells: population shifts and interactions with epithelial cells, linking cytokines (Ifn-γ, Il1B) with the aging of colonic epithelium. Our results provide new insights into the normal and age-associated states of the colon.
RESUMEN
Zimmermann-Laband syndrome is a rare, heterogeneous disorder characterized by gingival hypertrophy or fibromatosis, aplastic/hypoplastic nails, hypoplasia of the distal phalanges, hypertrichosis, various degrees of intellectual disability, and distinctive facial features. Three genes are considered causative for ZLS: KCNH1, KCNN3, and ATP6V1B2. We report on a pair of female concordant monozygotic twins, both carrying a novel pathogenic variant in the KCNN3 gene, identified using exome sequencing. Only six ZLS patients with the KCNN3 pathogenic variant have been reported so far. The twins show facial dysmorphism, hypoplastic distal phalanges, aplasia or hypoplasia of nails, and hypertrichosis. During infancy, they showed mild developmental delays, mainly speech. They successfully completed secondary school education and are socio-economically independent. Gingival overgrowth is absent in both individuals. Our patients exhibited an unusually mild phenotype compared to published cases, which is an important diagnostic finding for proper genetic counseling for Zimmermann-Laband syndrome patients and their families.
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Fibromatosis Gingival , Hipertricosis , Anomalías Múltiples , Anomalías Craneofaciales , Femenino , Fibromatosis Gingival/diagnóstico , Fibromatosis Gingival/genética , Deformidades Congénitas de la Mano , Humanos , Hiperplasia , Hipertricosis/genética , Uñas Malformadas/congénito , Fenotipo , Canales de Potasio de Pequeña Conductancia Activados por el Calcio/genética , Gemelos Monocigóticos/genéticaRESUMEN
α-Mangostin (aMan) and Paeonol (Pae) have shown anticancer and anti-inflammatory properties. However, these two natural compounds have no clinical value because of their low solubility and low membrane permeability. In this study, we screened chemically synthesized derivatives from these two natural compounds as potential novel chemicals that increase cancer cell cytotoxicity over nontransformed human cells. We found that two derivative compounds, named α-Mangostin-1 (aMan1) and Paeonol-1 (Pae1) more efficiently and more specifically induced cytotoxicity in HCT116, HT29, and SW48 colorectal cancer cell lines than the parental compounds. Both aMan1 and Pae1 arrested HCT116 cells in the G1 phase and HT29 and SW48 cells in the G2-M phase of the cell cycle. Both aMan1 and Pae1 induced apoptosis in human colorectal cancer cells, through a caspase-dependent mechanism. aMan1 and Pae1 induced selective transcriptional responses in colorectal cancer cells involving genes related to metabolic stress and DNA damage response signaling pathways. Finally, experiments on primary colon organoids showed that both derivatives were able to kill cancer-derived organoids without affecting the viability of organoids derived from healthy tissue, where the parental compounds and the currently used chemotherapeutic drug irinotecan failed. In conclusion, our findings expand the knowledge of natural compound derivatives as anticancer agents and open new avenues of research in the derivation of lead compounds aimed at developing novel chemotherapeutic drugs for colorectal cancer treatment that selectively target cancer, but not healthy cells.
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Acetofenonas/uso terapéutico , Antiinflamatorios/uso terapéutico , Antineoplásicos/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Xantonas/uso terapéutico , Acetofenonas/farmacología , Antiinflamatorios/farmacología , Antineoplásicos/farmacología , Proliferación Celular , Humanos , Inhibidores de Proteínas Quinasas/farmacología , Xantonas/farmacologíaRESUMEN
DNA methylation can regulate gene expression by modulating chromatin accessibility and transcription factor binding on promoter and enhancer regions. Whole-genome bisulfite sequencing (WGBS) represents the most informative and comprehensive analysis to profile the DNA methylation status of all the cytosines at single-base resolution. However, most of the available protocols recommend an amount of input DNA (50 ng-5µg) that makes the WGBS unsuitable for limited samples and cell populations. In this chapter, we provide complete protocol to perform WGBS libraries from very low-input DNA. This protocol is recommended for the analysis of the whole-genome DNA methylation pattern in rare cell populations, like a defined stem cell population isolated from animal models or human samples.
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Metilación de ADN , Epigénesis Genética , Epigenómica/métodos , Secuenciación Completa del Genoma/métodos , Biología Computacional/métodos , Islas de CpG , Elementos de Facilitación Genéticos , Biblioteca de Genes , Técnicas de Amplificación de Ácido Nucleico , Regiones Promotoras Genéticas , Programas InformáticosRESUMEN
Organoids culture provides unique opportunities to study human diseases and to complement animal models. Several organs and tissues can be in vitro cultured in 3D structures resembling in vivo tissue organization. Organoids culture contains most of the cell types of the original tissue and are maintained by growth factors mimicking the in vivo state. However, the system is yet not fully understood, and specific in vivo features especially those driven by cell-extrinsic factors may be lost in culture. Here we show a comprehensive transcriptome-wide characterization of mouse gut organoids derived from different intestinal compartments and from mice of different gender and age. RNA-seq analysis showed that the in vitro culture strongly influences the global transcriptome of the intestinal epithelial cells (~ 60% of the total variance). Several compartment-, age- and gender-related transcriptome features are lost after culturing indicating that they are driven by niche or systemic factors. However, certain intrinsic transcriptional programs, for example, some compartment-related features and a minority of gender- and aging- related features are maintained in vitro which suggested possibilities for these features to be studied in this system. Moreover, our study provides knowledge about the cell-extrinsic or cell-intrinsic origin of intestinal epithelial transcriptional programs. We anticipated that our characterization of this in vitro system is an important reference for scientists and clinicians using intestinal organoids as a research model.
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Intestino Delgado/metabolismo , Organoides/metabolismo , Transcriptoma , Animales , Células Cultivadas , Femenino , Perfilación de la Expresión Génica , Intestino Delgado/crecimiento & desarrollo , Masculino , Ratones Endogámicos C57BL , Organoides/crecimiento & desarrollo , Células Madre/metabolismo , Técnicas de Cultivo de TejidosRESUMEN
Dormancy, a reversible quiescent cellular state characterized by greatly reduced metabolic activity, protects from genetic damage, prolongs survival and is crucial for tissue homeostasis and cellular response to injury or transplantation. Dormant cells have been characterized in many tissues, but their identification, isolation and characterization irrespective of tissue of origin remains elusive. Here, we develop a live cell ratiometric fluorescent Optical Stem Cell Activity Reporter (OSCAR) based on the observation that phosphorylation of RNA Polymerase II (RNApII), a hallmark of active mRNA transcription elongation, is largely absent in dormant stem cells from multiple lineages. Using the small intestinal crypt as a model, OSCAR reveals in real time the dynamics of dormancy induction and cellular differentiation in vitro, and allows the identification and isolation of several populations of transcriptionally diverse OSCARhigh and OSCARlow intestinal epithelial cell states in vivo. In particular, this reporter is able to identify a dormant OSCARhigh cell population in the small intestine. OSCAR therefore provides a tool for a better understanding of dormant stem cell biology.
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ARN Polimerasa II/metabolismo , Fase de Descanso del Ciclo Celular/fisiología , Animales , Separación Celular , Quinasa 9 Dependiente de la Ciclina/metabolismo , Citometría de Flujo , Colorantes Fluorescentes/metabolismo , Humanos , Mucosa Intestinal/citología , Mucosa Intestinal/metabolismo , Intestino Delgado/citología , Intestino Delgado/metabolismo , Proteínas Luminiscentes/metabolismo , Ratones , Ratones Transgénicos , ARN Mensajero/metabolismo , Transcripción GenéticaRESUMEN
Brain homeostasis is regulated by the viability and functionality of neurons. HAT (histone acetyltransferase) and HDAC (histone deacetylase) inhibitors have been applied to treat neurological deficits in humans; yet, the epigenetic regulation in neurodegeneration remains elusive. Mutations of HAT cofactor TRRAP (transformation/transcription domain-associated protein) cause human neuropathies, including psychosis, intellectual disability, autism, and epilepsy, with unknown mechanism. Here we show that Trrap deletion in Purkinje neurons results in neurodegeneration of old mice. Integrated transcriptomics, epigenomics, and proteomics reveal that TRRAP via SP1 conducts a conserved transcriptomic program. TRRAP is required for SP1 binding at the promoter proximity of target genes, especially microtubule dynamics. The ectopic expression of Stathmin3/4 ameliorates defects of TRRAP-deficient neurons, indicating that the microtubule dynamics is particularly vulnerable to the action of SP1 activity. This study unravels a network linking three well-known, but up-to-date unconnected, signaling pathways, namely TRRAP, HAT, and SP1 with microtubule dynamics, in neuroprotection.
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Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Factor de Transcripción Sp1/genética , Factor de Transcripción Sp1/metabolismo , Envejecimiento , Animales , Epigénesis Genética , Eliminación de Gen , Regulación de la Expresión Génica , Ratones , Ratones Mutantes , Microtúbulos/metabolismo , Células de Purkinje/patología , Transducción de SeñalRESUMEN
Aging associates with progressive loss of skeletal muscle function, sometimes leading to sarcopenia, a process characterized by impaired mobility and weakening of muscle strength. Since aging associates with profound epigenetic changes, epigenetic landscape alteration analysis in the skeletal muscle promises to highlight molecular mechanisms of age-associated alteration in skeletal muscle. This study was conducted exploiting the short-lived turquoise killifish Nothobranchius furzeri (Nfu), a relatively new model for aging studies. The epigenetic analysis suggested a less accessible and more condensed chromatin in old Nfu skeletal muscle. Specifically, an accumulation of heterochromatin regions was observed as a consequence of increased levels of H3K27me3, HP1α, polycomb complex subunits, and senescence-associated heterochromatic foci (SAHFs). Consistently, euchromatin histone marks, including H3K9ac, were significantly reduced. In this context, integrated bioinformatics analysis of RNASeq and ChIPSeq, related to skeletal muscle of Nfu at different ages, revealed a down-modulation of genes involved in cell cycle, differentiation, and DNA repair and an up-regulation of inflammation and senescence genes. Undoubtedly, more studies are needed to disclose the detailed mechanisms; however, our approach enlightened unprecedented features of Nfu skeletal muscle aging, potentially associated with swimming impairment and reduced mobility typical of old Nfu.
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Envejecimiento/genética , Metilación de ADN , Proteínas de Peces/genética , Heterocromatina/metabolismo , Histonas/metabolismo , Músculo Esquelético/metabolismo , Acetilación , Envejecimiento/metabolismo , Animales , Secuenciación de Inmunoprecipitación de Cromatina , Homólogo de la Proteína Chromobox 5 , Proteínas Cromosómicas no Histona/genética , Ciprinodontiformes , Epigénesis Genética , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Heterocromatina/genética , Masculino , Modelos Biológicos , Análisis de Secuencia de ARNRESUMEN
BACKGROUND: The complete androgen insensitivity syndrome (CAIS) is a rare genetic disorder causing insensitivity to androgens in a person with female phenotype and 46,XY karyotype due to a mutation in the androgen receptor gene located on chromosome X. These children are born with female external genitalia, and females are transmitters. CASE REPORT: We illustrate an unexpected diagnosis of CAIS in two siblings during examination for short stature, and describe transmission/carriers in the family along with ethical aspects. CONCLUSION: A genetic examination could have earlier revealed the transmission of c.2495G>Tp.(Arg832Leu) mutation in exon 7. Our experience highlights the possibility of prenatal testing for the management of pregnancy in a family with a history of CAIS. The implications of prenatal testing in relation to CAIS with clearer explication of ethical and clinical issues warrant further investigation.
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Síndrome de Resistencia Androgénica/diagnóstico , Síndrome de Resistencia Androgénica/genética , Trastornos del Desarrollo Sexual/diagnóstico , Trastornos del Desarrollo Sexual/genética , Desarrollo Fetal/genética , Transferencia de Gen Horizontal , Receptores Androgénicos/genética , Síndrome de Resistencia Androgénica/fisiopatología , Trastornos del Desarrollo Sexual/fisiopatología , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , MutaciónRESUMEN
Kabuki syndrome is mainly caused by dominant de-novo pathogenic variants in the KMT2D and KDM6A genes. The clinical features of this syndrome are highly variable, making the diagnosis of Kabuki-like phenotypes difficult, even for experienced clinical geneticists. Herein we present molecular genetic findings of causal genetic variation using array comparative genome hybridization and a Mendeliome analysis, utilizing targeted exome analysis focusing on regions harboring rare disease-causing variants in Kabuki-like patients which remained KMT2D/KDM6A-negative. The aCGH analysis revealed a pathogenic CNV in the 14q11.2 region, while targeted exome sequencing revealed pathogenic variants in genes associated with intellectual disability (HUWE1, GRIN1), including a gene coding for mandibulofacial dysostosis with microcephaly (EFTUD2). Lower values of the MLL2-Kabuki phenotypic score are indicative of Kabuki-like phenotype (rather than true Kabuki syndrome), where aCGH and Mendeliome analyses have high diagnostic yield. Based on our findings we conclude that for new patients with Kabuki-like phenotypes it is possible to choose a specific molecular testing approach that has the highest detection rate for a given MLL2-Kabuki score, thus fostering more precise patient diagnosis and improved management in these genetically- and phenotypically heterogeneous clinical entities.
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Anomalías Múltiples/genética , Cara/anomalías , Heterogeneidad Genética , Genotipo , Enfermedades Hematológicas/genética , Fenotipo , Enfermedades Vestibulares/genética , Anomalías Múltiples/diagnóstico , Anomalías Múltiples/fisiopatología , Niño , Preescolar , Cromosomas Humanos Par 14 , Hibridación Genómica Comparativa , Proteínas de Unión al ADN/genética , Exoma , Cara/fisiopatología , Femenino , Enfermedades Hematológicas/diagnóstico , Enfermedades Hematológicas/fisiopatología , Secuenciación de Nucleótidos de Alto Rendimiento , Histona Demetilasas/genética , Humanos , Discapacidad Intelectual/genética , Masculino , Disostosis Mandibulofacial/genética , Microcefalia/genética , Proteínas de Neoplasias/genética , Proteínas del Tejido Nervioso/genética , Proteínas Nucleares/genética , Factores de Elongación de Péptidos/genética , Receptores de N-Metil-D-Aspartato/genética , Ribonucleoproteína Nuclear Pequeña U5/genética , Proteínas Supresoras de Tumor/genética , Ubiquitina-Proteína Ligasas/genética , Enfermedades Vestibulares/diagnóstico , Enfermedades Vestibulares/fisiopatologíaRESUMEN
NF-κB is a transcription factor involved in the regulation of multiple physiological and pathological cellular processes, including inflammation, cell survival, proliferation, and cancer cell metastasis. NF-κB is frequently hyperactivated in several cancers, including triple-negative breast cancer. Here we show that NF-κB activation in breast cancer cells depends on the presence of the CHORDC1 gene product Morgana, a previously unknown component of the IKK complex and essential for IκBα substrate recognition. Morgana silencing blocks metastasis formation in breast cancer mouse models and this phenotype is reverted by IκBα downregulation. High Morgana expression levels in cancer cells decrease recruitment of natural killer cells in the first phases of tumor growth and induce the expression of cytokines able to attract neutrophils in the primary tumor, as well as in the pre-metastatic lungs, fueling cancer metastasis. In accordance, high Morgana levels positively correlate with NF-κB target gene expression and poor prognosis in human patients.