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BACKGROUND: Dachsous cadherin related 1 (DCHS1) is one of calcium-dependent adhesion membrane proteins and is mainly involved in the development of mammalian tissues. There is a lack of more detailed research on the biological function of DCHS1 in pan-cancer. MATERIALS AND METHODS: We evaluated the expression, the prognostic value, the diagnostic value and genomic alterations of DCHS1 by using the databases, including TCGA, UALCAN, HPA, GEPIA2.0 and GSCA. We employed the databases of UCSC, TIMER2.0, TISIDB, GSCA to analyze the association between DCHS1 expression and the immune microenvironment, stemness, TMB, MSI and anticancer drug sensitivity. BioGRID, STRING and GEPIA2.0 were used to perform protein interaction and functional enrichment analysis. Real-time quantitative PCR, CCK8, Transwell assay and Western blot were performed to determine the function of DCHS1 in UCEC. RESULTS: DCHS1 is differentially expressed in many cancers and its expression is significantly associated with tumor prognosis and diagnosis. DCHS1 expression was significantly correlated with the infiltration of cancer-associated fibroblasts (CAFs), Endothelial cell (ECs), and Hematopoietic stem cell in most cancers. In addition, DCHS1 was significantly associated with sensitivity to many antitumor drugs. Functional enrichment analysis revealed that DCHS1-related proteins were involved in Focal adhesion, Endometrial cancer and Wnt signaling pathway. GSEA results showed that DCHS1 was related to epithelial-mesenchymal transition (EMT) in many cancers. In vitro experiments in UCEC showed that DCHS1 regulated cell proliferation, migration and EMT. CONCLUSIONS: Our findings indicated that DCHS1 might be a novel prognostic and diagnostic biomarker and immunotherapy target, and plays an important role in the proliferation, migration and EMT in UCEC.
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Biomarcadores de Tumor , Neoplasias Endometriales , Transición Epitelial-Mesenquimal , Femenino , Humanos , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/genética , Proteínas Relacionadas con las Cadherinas , Línea Celular Tumoral , Neoplasias Endometriales/metabolismo , Neoplasias Endometriales/genética , Neoplasias Endometriales/patología , Neoplasias Endometriales/inmunología , Regulación Neoplásica de la Expresión Génica , Pronóstico , Microambiente Tumoral/inmunologíaRESUMEN
Randall's plaques (RP) serve as anchoring sites for calcium oxalate (CaOx) stones, but the underlying mechanism remains unclear. Renal interstitium with a high-calcium environment is identified as pathogenesis of RP formation where the role of human renal interstitial fibroblasts (hRIFs) was highlighted. Our study aims to elucidate the potential mechanism by which a high-calcium environment drives ectopic calcification of hRIFs to participate in RP formation. Alizarin Red staining demonstrated calcium nodules in hRIFs treated with high-calcium medium. Utilizing transcriptome sequencing, tissue factor pathway inhibitor-2 (TFPI-2) was found to be upregulated in high-calcium-induced hRIFs and RP tissues, and TFPI-2 promoted high-calcium-induced calcification of hRIFs. Subsequently, the downstream regulator of TFPI2 was screened by transcriptome sequencing analysis of hRIFs with TFPI-2 knockdown or overexpressed. Dachsous Cadherin Related 1 (DCHS1) knockdown was identified to suppress the calcification of hRIFs enhanced by TFPI-2. Further investigation revealed that TFPI-2/DCHS1 axis promoted high-calcium-induced calcification of hRIFs via disturbing the balance of ENPP1/ALP activities, but without effect on the canonical osteogenic markers, such as osteopontin (OPN), osteogenic factors runt-related transcription factor 2 (RUNX2), bone morphogenetic protein 2 (BMP2). In summary, our study mimicked the high-calcium environment observed in CaOx stone patients with hypercalciuria, and discovered that the high-calcium drove ectopic calcification of hRIFs via a novel TFPI-2-DCHS1-ALP/ENPP1 pathway rather than adaption of osteogenic phenotypes to participate in RP formation.
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Calcinosis , Fibroblastos , Glicoproteínas , Humanos , Calcinosis/patología , Calcinosis/metabolismo , Fibroblastos/metabolismo , Fibroblastos/patología , Glicoproteínas/metabolismo , Glicoproteínas/genética , Calcio/metabolismo , Riñón/patología , Riñón/metabolismo , Fosfatasa Alcalina/metabolismo , Cálculos Renales/metabolismo , Cálculos Renales/patología , Cálculos Renales/etiología , Cálculos Renales/genética , Células CultivadasRESUMEN
Periventricular neuronal heterotopia (PH) is one of the most common forms of cortical malformation in the human cortex. We show that human neuronal progenitor cells (hNPCs) derived from PH patients with a DCHS1 or FAT4 mutation as well as isogenic lines had altered migratory dynamics when grafted in the mouse brain. The affected migration was linked to altered autophagy as observed in vivo with an electron microscopic analysis of grafted hNPCs, a Western blot analysis of cortical organoids, and time-lapse imaging of hNPCs in the presence of bafilomycin A1. We further show that deficits in autophagy resulted in the accumulation of paxillin, a focal adhesion protein involved in cell migration. Strikingly, a single-cell RNA-seq analysis of hNPCs revealed similar expression levels of autophagy-related genes. Bolstering AMPK-dependent autophagy by metformin, an FDA-approved drug, promoted migration of PH patients-derived hNPCs. Our data indicate that transcription-independent homeostatic modifications in autophagy contributed to the defective migratory behavior of hNPCs in vivo and suggest that modulating autophagy in hNPCs might rescue neuronal migration deficits in some forms of PH.
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The aggressive features of glioblastoma (GBM) are associated with dormancy. Our previous transcriptome analysis revealed that several genes were regulated during temozolomide (TMZ)-promoted dormancy in GBM. Focusing on genes involved in cancer progression, Chemokine (C-C motif) Receptor-Like (CCRL)1, Schlafen (SLFN)13, Sloan-Kettering Institute (SKI), Cdk5 and Abl Enzyme Substrate (Cables)1, and Dachsous Cadherin-Related (DCHS)1 were selected for further validation. All showed clear expression and individual regulatory patterns under TMZ-promoted dormancy in human GBM cell lines, patient-derived primary cultures, glioma stem-like cells (GSCs), and human GBM ex vivo samples. All genes exhibited complex co-staining patterns with different stemness markers and with each other, as examined by immunofluorescence staining and underscored by correlation analyses. Neurosphere formation assays revealed higher numbers of spheres during TMZ treatment, and gene set enrichment analysis of transcriptome data revealed significant regulation of several GO terms, including stemness-associated ones, indicating an association between stemness and dormancy with the involvement of SKI. Consistently, inhibition of SKI during TMZ treatment resulted in higher cytotoxicity, proliferation inhibition, and lower neurosphere formation capacity compared to TMZ alone. Overall, our study suggests the involvement of CCRL1, SLFN13, SKI, Cables1, and DCHS1 in TMZ-promoted dormancy and demonstrates their link to stemness, with SKI being particularly important.
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Neoplasias Encefálicas , Glioblastoma , Humanos , Temozolomida/farmacología , Glioblastoma/tratamiento farmacológico , Glioblastoma/genética , Línea Celular Tumoral , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Regulación Neoplásica de la Expresión GénicaRESUMEN
Cell growth and patterning are critical for tissue development. Here we discuss the evolutionarily conserved cadherins, Fat and Dachsous, and the roles they play during mammalian tissue development and disease. In Drosophila, Fat and Dachsous regulate tissue growth via the Hippo pathway and planar cell polarity (PCP). The Drosophila wing has been an ideal tissue to observe how mutations in these cadherins affect tissue development. In mammals, there are multiple Fat and Dachsous cadherins, which are expressed in many tissues, but mutations in these cadherins that affect growth and tissue organization are context dependent. Here we examine how mutations in the Fat and Dachsous mammalian genes affect development in mammals and contribute to human disease.
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Cadherinas , Proteínas de Drosophila , Animales , Humanos , Cadherinas/genética , Cadherinas/metabolismo , Drosophila/genética , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Crecimiento y Desarrollo , Proliferación Celular , Polaridad Celular/genética , Drosophila melanogaster , Mamíferos/genética , Mamíferos/metabolismoRESUMEN
Mitral valve prolapse (MVP) is a common cardiac valve disease that often progresses to serious secondary complications requiring surgery. MVP manifests as extracellular matrix disorganization and biomechanically incompetent tissues in the adult setting. However, MVP has recently been shown to have a developmental basis, as multiple causal genes expressed during embryonic development have been identified. Disease phenotypes have been observed in mouse models with human MVP mutations as early as birth. This study focuses on the developmental function of DCHS1, one of the first genes to be shown as causal in multiple families with non-syndromic MVP. By using various biochemical techniques as well as mouse and cell culture models, we demonstrate a unique link between DCHS1-based cell adhesions and the septin-actin cytoskeleton through interactions with cytoplasmic protein Lix1-Like (LIX1L). This DCHS1-LIX1L-SEPT9 axis interacts with and promotes filamentous actin organization to direct cell-ECM alignment and valve tissue shape.
RESUMEN
BACKGROUND: Mitral valve prolapse (MVP) is a common cardiovascular disease defined as a late systolic click or mitral valve lobes that move up into the left atrium during ventricular systole, with or without mitral insufficiency. Dachsous catherin-related 1 (DCHS1) is one of the two known pathogenic genes associated with MVP. However, there is little information about the renal dysfunction caused by MVP and DCHS1 mutations. METHODS: We analyzed the genetic etiology in a rare case of 9-year-old boy affected by chronic renal failure with MVP. Subsequently, we constructed stable cell lines overexpressing wild-type DCHS1 or mutant DCHS1 (c.8309G>A, p.R2770Q) to evaluate the influence of the DCHS1 mutation on the proliferation, apoptosis, and autophagy. RESULTS: Complete exome sequencing and pedigree verification revealed a mutation p.R2770Q (c.8309G>A) in exon 21 of the DCHS1 gene carried by the patient, which may affect the DNA binding. No such mutation was detected in his parents, indicating that this was a new mutation. Potential functional impact of sequence variants was predicted using in silico prediction programs including SIFT, Polyphen2, and Condel. This variant was determined to be a pathogenic mutation that has not been reported elsewhere. Subsequently, we used a stable DCHS1 gene-mutated HK-2 cell line to analyse proliferation, apoptosis, and autophagy, showed that kidney volume decreased with increasing cell death associated with a reduced proliferation. CONCLUSIONS: Our analysis revealed a heterozygous variation of DCHS1 in a child with MVP. Our observations highlight previously unrecognized phenotypes of the currently recognized MVP genotype, including distinct chronic renal failure.
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Cadherinas/genética , Prolapso de la Válvula Mitral/genética , Mutación Missense , Fenotipo , Insuficiencia Renal Crónica/genética , Apoptosis , Proteínas Relacionadas con las Cadherinas , Cadherinas/metabolismo , Línea Celular , Proliferación Celular , Niño , Humanos , Masculino , Prolapso de la Válvula Mitral/patología , Insuficiencia Renal Crónica/patologíaAsunto(s)
Insuficiencia de la Válvula Mitral , Prolapso de la Válvula Mitral , Predisposición Genética a la Enfermedad , Humanos , Insuficiencia de la Válvula Mitral/genética , Insuficiencia de la Válvula Mitral/cirugía , Prolapso de la Válvula Mitral/diagnóstico por imagen , Prolapso de la Válvula Mitral/genética , FenotipoRESUMEN
In human, mutations of the protocadherins FAT4 and DCHS1 result in Van Maldergem syndrome, which is characterised, in part, by craniofacial abnormalities. Here, we analyse the role of Dchs1-Fat4 signalling during osteoblast differentiation in mouse. We show that Fat4 and Dchs1 mutants mimic the craniofacial phenotype of the human syndrome and that Dchs1-Fat4 signalling is essential for osteoblast differentiation. In Dchs1/Fat4 mutants, proliferation of osteoprogenitors is increased and osteoblast differentiation is delayed. We show that loss of Dchs1-Fat4 signalling is linked to increased Yap-Tead activity and that Yap is expressed and required for proliferation in osteoprogenitors. In contrast, Taz is expressed in more-committed Runx2-expressing osteoblasts, Taz does not regulate osteoblast proliferation and Taz-Tead activity is unaffected in Dchs1/Fat4 mutants. Finally, we show that Yap and Taz differentially regulate the transcriptional activity of Runx2, and that the activity of Yap-Runx2 and Taz-Runx2 complexes is altered in Dchs1/Fat4 mutant osteoblasts. In conclusion, these data identify Dchs1-Fat4 as a signalling pathway in osteoblast differentiation, reveal its crucial role within the early Runx2 progenitors, and identify distinct requirements for Yap and Taz during osteoblast differentiation.
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Cadherinas/fisiología , Osteoblastos/fisiología , Osteogénesis/genética , Anomalías Múltiples/genética , Anomalías Múltiples/patología , Animales , Animales Recién Nacidos , Diferenciación Celular/genética , Células Cultivadas , Anomalías Craneofaciales/genética , Anomalías Craneofaciales/patología , Modelos Animales de Enfermedad , Embrión de Mamíferos , Femenino , Deformidades Congénitas del Pie/genética , Deformidades Congénitas del Pie/patología , Deformidades Congénitas de la Mano/genética , Deformidades Congénitas de la Mano/patología , Humanos , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Inestabilidad de la Articulación/genética , Inestabilidad de la Articulación/patología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Embarazo , Transducción de Señal/genéticaRESUMEN
Biallelic variants in FAT4 are associated with the two disorders, Van Maldergem syndrome (VMS) (n = 11) and Hennekam syndrome (HS) (n= 40). Both conditions are characterized by a typical facial gestalt and mild to moderate intellectual disability, but differ in the occurrence of neonatal hypotonia and feeding problems, hearing loss, tracheal anomalies, and osteopenia in VMS, and lymphedema in HS. VMS can be caused by autosomal recessive variants in DCHS1 as well, and HS can also be caused by autosomal recessive variants in CCBE1 and ADAMTS3. Here we report two siblings with VMS and one girl with HS, all with FAT4 variants, and provide an overview of the clinical findings in all patients reported with FAT4 variants. Our comparison of the complete phenotypes of patients with VMS and HS indicates a resemblance of several signs, but differences in several other main signs and symptoms, each of marked importance for affected individuals.
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Anomalías Múltiples/diagnóstico , Anomalías Múltiples/genética , Alelos , Anomalías Craneofaciales/diagnóstico , Anomalías Craneofaciales/genética , Deformidades Congénitas del Pie/diagnóstico , Deformidades Congénitas del Pie/genética , Estudios de Asociación Genética , Deformidades Congénitas de la Mano/diagnóstico , Deformidades Congénitas de la Mano/genética , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Inestabilidad de la Articulación/diagnóstico , Inestabilidad de la Articulación/genética , Fenotipo , Huesos/anomalías , Huesos/diagnóstico por imagen , Encéfalo/anomalías , Encéfalo/diagnóstico por imagen , Cadherinas/genética , Proteínas de Unión al Calcio/genética , Niño , Preescolar , Hibridación Genómica Comparativa , Facies , Femenino , Estudios de Asociación Genética/métodos , Genotipo , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Lactante , Recién Nacido , Masculino , Mutación , Radiografía , Hermanos , Proteínas Supresoras de Tumor/genéticaRESUMEN
BACKGROUND: A recent study identified DCHS1 as a causal gene for mitral valve prolapse. The goal of this study is to investigate the presence and frequency of known and novel variants in this gene in 100 asymptomatic patients with moderate to severe organic mitral regurgitation. METHODS: DNA sequencing assays were developed for two previously identified functional missense variants, namely p.R2330C and p.R2513H, and all 21 exons of DCHS1. Pathogenicity of variants was evaluated in silico. RESULTS: p.R2330C and p.R2513H were not identified in this cohort. Sequencing all coding regions revealed eight missense variants including six considered deleterious. This includes one novel variant (p.A2464P) and two rare variants (p.R2770Q and p.R2462Q). These variants are predicted to be deleterious with combined annotation-dependent depletion (CADD) scores greater than 25, which are in the same range as p.R2330C (CADD = 28.0) and p.R2513H (CADD = 24.3). More globally, 24 of 100 cases were carriers of at least one in silico-predicted deleterious missense variant in DCHS1, suggesting that this single gene may account for a substantial portion of cases. CONCLUSION: This study reveals an important contribution of germline variants in DCHS1 in unrelated patients with mitral valve prolapse and supports genetic testing of this gene to screen individuals at risk.
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Cadherinas/genética , Insuficiencia de la Válvula Mitral/genética , Prolapso de la Válvula Mitral/genética , Adulto , Anciano , Anciano de 80 o más Años , Proteínas Relacionadas con las Cadherinas , Cadherinas/fisiología , Estudios de Cohortes , Simulación por Computador , Exones , Femenino , Pruebas Genéticas , Variación Genética/genética , Humanos , Mutación con Pérdida de Función/genética , Masculino , Persona de Mediana Edad , Prevalencia , QuebecRESUMEN
BACKGROUND: We report a female patient with endocrine abnormalities, hypogonadotropic hypogonadism and amazia (breasts aplasia/hypoplasia but normal nipples and areolas) in a rare syndrome: Van Maldergem syndrome (VMS). CASE PRESENTATION: Our patient was first evaluated at age 4 for intellectual disability, craniofacial features, and auditory malformations. At age 15, she presented with no breast development and other findings consistent with hypogonadotropic hypogonadism. At age 37, she underwent whole exome sequencing (WES) to identify pathogenic variants. WES revealed compound heterozygous variants in DCHS1 (rs145099391:G > A, p.P197L & rs753548138:G > A, p.T2334 M) [RefSeq NM_003737.3], diagnostic of Van Maldergem syndrome (VMS-1). VMS is a rare autosomal disorder reported in only 13 patients, characterized by intellectual disability, typical craniofacial features, auditory malformations, hearing loss, skeletal and limb malformations, brain abnormalities with periventricular neuronal heterotopia and other variable anomalies. Our patient had similar phenotypic abnormalities. She also had hypogonadotropic hypogonadism and amazia. Based on the clinical findings reported, two previously published patients with VMS may also have been affected by hypogonadotropic hypogonadism, but endocrine abnormalities were not evaluated or mentioned. CONCLUSION: This case highlights an individual with VMS, characterized by compound heterozygous variants in DCHS1. Our observations may provide additional information on the phenotypic spectrum of VMS, including hypogonadotropic hypogonadism and amazia. However, the molecular genetic basis for endocrine anomalies observed in some VMS patients, including ours, remains unexplained.
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The protocadherins Fat4 and Dchs1 act as a receptor-ligand pair to regulate many developmental processes in mice and humans, including development of the vertebrae. Based on conservation of function between Drosophila and mammals, Fat4-Dchs1 signalling has been proposed to regulate planar cell polarity (PCP) and activity of the Hippo effectors Yap and Taz, which regulate cell proliferation, survival and differentiation. There is strong evidence for Fat regulation of PCP in mammals but the link with the Hippo pathway is unclear. In Fat4(-/-) and Dchs1(-/-) mice, many vertebrae are split along the midline and fused across the anterior-posterior axis, suggesting that these defects might arise due to altered cell polarity and/or changes in cell proliferation/differentiation. We show that the somite and sclerotome are specified appropriately, the transcriptional network that drives early chondrogenesis is intact, and that cell polarity within the sclerotome is unperturbed. We find that the key defect in Fat4 and Dchs1 mutant mice is decreased proliferation in the early sclerotome. This results in fewer chondrogenic cells within the developing vertebral body, which fail to condense appropriately along the midline. Analysis of Fat4;Yap and Fat4;Taz double mutants, and expression of their transcriptional target Ctgf, indicates that Fat4-Dchs1 regulates vertebral development independently of Yap and Taz. Thus, we have identified a new pathway crucial for the development of the vertebrae and our data indicate that novel mechanisms of Fat4-Dchs1 signalling have evolved to control cell proliferation within the developing vertebrae.
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Cadherinas/metabolismo , Transducción de Señal , Columna Vertebral/citología , Columna Vertebral/embriología , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Proteínas de Ciclo Celular , Polaridad Celular , Proliferación Celular , Ratones Mutantes , Morfogénesis , Mutación/genética , Fosfoproteínas/metabolismo , Columna Vertebral/metabolismo , Transactivadores , Proteínas Señalizadoras YAPRESUMEN
Dachsous (Dchs), an atypical cadherin, is an evolutionarily conserved regulator of planar cell polarity, tissue size and cell adhesion. In humans, DCHS1 mutations cause pleiotropic Van Maldergem syndrome. Here, we report that mutations in zebrafish dchs1b and dchs2 disrupt several aspects of embryogenesis, including gastrulation. Unexpectedly, maternal zygotic (MZ) dchs1b mutants show defects in the earliest developmental stage, egg activation, including abnormal cortical granule exocytosis (CGE), cytoplasmic segregation, cleavages and maternal mRNA translocation, in transcriptionally quiescent embryos. Later, MZdchs1b mutants exhibit altered dorsal organizer and mesendodermal gene expression, due to impaired dorsal determinant transport and Nodal signaling. Mechanistically, MZdchs1b phenotypes can be explained in part by defective actin or microtubule networks, which appear bundled in mutants. Accordingly, disruption of actin cytoskeleton in wild-type embryos phenocopied MZdchs1b mutant defects in cytoplasmic segregation and CGE, whereas interfering with microtubules in wild-type embryos impaired dorsal organizer and mesodermal gene expression without perceptible earlier phenotypes. Moreover, the bundled microtubule phenotype was partially rescued by expressing either full-length Dchs1b or its intracellular domain, suggesting that Dchs1b affects microtubules and some developmental processes independent of its known ligand Fat. Our results indicate novel roles for vertebrate Dchs in actin and microtubule cytoskeleton regulation in the unanticipated context of the single-celled embryo.