An uncharacterized gene, C7orf26, identified from an autosomal dominant ocular disease functions in mRNA splicing
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ABSTRACT:
PROVIDER: PRJNA773402 | ENA |
REPOSITORIES: ENA
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Project description:An uncharacterized gene, C7orf26 was expected to function with the integrator complex in mRNA splicing. To address the involvement of mRNA splicing, we performed microarray analysis of HeLa/C7orf26 siRNA cells and HeLa/non-specific (NS) and identified 700 transcripts that were downregulated by 50% or more in C7orf26 siRNA-treated HeLa cells. Gene set enrichment analysis showed that genes tagged with ‘alternative splicing’ or ‘splice variant’ occupy a large fraction of the downregulated genes.
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Project description:Background: Autosomal dominant polycystic kidney disease (ADPKD) affects more than 12 million people worldwide. Mutations in PKD1 and PKD2 cause cyst formation through unknown mechanisms. To unravel the pathogenic mechanisms in ADPKD, multiple studies have investigated transcriptional mis-regulation in cystic kidneys from patients and mouse models, and numerous dysregulated genes and pathways have been described. Yet, the concordance between studies has been rather limited. Furthermore, the cellular and genetic diversity in cystic kidneys has hampered the identification of mis-expressed genes in kidney epithelial cells with homozygous PKD mutations, which are critical to identify polycystin-dependent pathways. Methods: Autosomal dominant polycystic kidney disease (ADPKD) affects more than 12 million people worldwide. Mutations in PKD1 and PKD2 cause cyst formation through unknown mechanisms. To unravel the pathogenic mechanisms in ADPKD, multiple studies have investigated transcriptional mis-regulation in cystic kidneys from patients and mouse models, and numerous dysregulated genes and pathways have been described. Yet, the concordance between studies has been rather limited. Furthermore, the cellular and genetic diversity in cystic kidneys has hampered the identification of mis-expressed genes in kidney epithelial cells with homozygous PKD mutations, which are critical to identify polycystin-dependent pathways. Results: Autosomal dominant polycystic kidney disease (ADPKD) affects more than 12 million people worldwide. Mutations in PKD1 and PKD2 cause cyst formation through unknown mechanisms. To unravel the pathogenic mechanisms in ADPKD, multiple studies have investigated transcriptional mis-regulation in cystic kidneys from patients and mouse models, and numerous dysregulated genes and pathways have been described. Yet, the concordance between studies has been rather limited. Furthermore, the cellular and genetic diversity in cystic kidneys has hampered the identification of mis-expressed genes in kidney epithelial cells with homozygous PKD mutations, which are critical to identify polycystin-dependent pathways. Conclusions: Autosomal dominant polycystic kidney disease (ADPKD) affects more than 12 million people worldwide. Mutations in PKD1 and PKD2 cause cyst formation through unknown mechanisms. To unravel the pathogenic mechanisms in ADPKD, multiple studies have investigated transcriptional mis-regulation in cystic kidneys from patients and mouse models, and numerous dysregulated genes and pathways have been described. Yet, the concordance between studies has been rather limited. Furthermore, the cellular and genetic diversity in cystic kidneys has hampered the identification of mis-expressed genes in kidney epithelial cells with homozygous PKD mutations, which are critical to identify polycystin-dependent pathways.
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Project description:ADPKD (Autosomal dominant polycystic kidney disease) is the most common inherited disorders and is characterized by growth of numerous cysts filled with fluid in the kidneys. Ultimately, it leads to kidney failure. The mutations of PKD1 and PKD2 account for approximately 85 and 15 percent of ADPKD, respectively. However, the mechanisms related to genetic mutation of PKD1 and PKD2 are still unclear. To investigate altered gene expression levels, Affymetrix microarray was performed using the kidney tissue from normal and ADPKD patients.
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Project description:The heterogeneous etiology of Alzheimer’s disease (AD) challenges therapeutic development. Understanding cell type specificity and local spatial contributions to different AD etiologies is instrumental to optimize therapeutic strategies for precision medicine. In this study, we compared cell-specific transcriptomes from the frontal cortex of carriers with the autosomal dominant mutation, PSEN1-E280A, sporadic AD and controls. Among the pathways that distinguished the autosomal dominant AD mutation disease from sporadic AD was increased autophagy and proteostasis pathways in astrocytes and oligodendrocytes in the former. Synaptic genes associated with neurofibrillary tangles in excitatory neurons were increased in both sporadic AD and mutation carriers. Spatial transcriptomics in samples from frontal cortex and CA1 hippocampus in PSEN1-E280A cases compared to non-diseased control individuals further validated the activation of chaperone-mediated autophagy genes and NFT-associated genes in E280A cases compared to controls. In conclusion, although autosomal dominant Alzheimer’s disease (ADAD) and sporadic AD share many features, the uniqueness of the cellular responses in each condition must be taken into consideration when designing clinical studies and therapeutics.
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Project description:The heterogeneous etiology of Alzheimer’s disease (AD) challenges therapeutic development. Understanding cell type gene expression specificity and local spatial contributions to different AD etiologies is instrumental to optimize therapeutic strategies for precision medicine. In this study, we compared cell-specific transcriptomes from the frontal cortex of carriers with the autosomal dominant mutation, PSEN1-E280A, Sporadic AD and Controls. Among the pathways that distinguished the autosomal dominant AD mutation disease from sporadic AD was increased autophagy and proteostasis pathways in astrocytes and oligodendrocytes in the former. Synaptic genes associated with neurofibrillary tangles in excitatory neurons were increased in both sporadic AD and mutation carriers. Spatial transcriptomics in samples from frontal cortex and CA1 hippocampus in PSEN1-E280A cases compared to non-diseased control individuals further validated the activation of chaperone-mediated autophagy genes and NFT-associated genes in E280A cases compared to controls. In conclusion, although autosomal dominant Alzheimer’s disease (ADAD) and sporadic AD share many features, the uniqueness of the cellular responses in each condition must be taken into consideration when designing clinical studies and therapeutics.
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Project description:The molecular cause of severe congenital neutropenia (SCN) is unknown in 30-50% of patients. SEC61A1 encodes the α subunit of the heterotrimeric SEC61 complex, which governs endoplasmic reticulum (ER) signal peptide-dependent protein transport and passive calcium leakage. Recently, autosomal dominant mutations in SEC61A1 were reported to be pathogenic in common variable immunodeficiency (CVID) and glomerulocystic kidney disease. However the full spectrum of clinical manifestations in SEC61A1 mutations is yet to be explored. We investigated a SCN patient, the only child of healthy non-consanguineous Belgian parents. We identified a de novo private missense mutation in SEC61A1 (c.A275G;p.Q92R; CADD 24.5; msc 6.099) in the patient. The mutation results in diminished expression of the protein in PBMC and fibroblasts, and an increase in calcium leakage from the ER. In vitro differentiation of CD34+ cells recapitulated the patient’s clinical arrest in granulopoiesis. The impact of Q92R-SEC61α1 on neutrophil maturation was validated using HL-60 cells, where transduction reduced differentiation into CD11b+CD16+ cells. A potential mechanism for this defect is the uncontrolled initiation of the unfolded protein stress response (UPR), with single-cell analysis of primary bone-marrow revealing perturbed UPR in myeloid precursors, and in vitro differentiation of primary CD34+ cells into neutrophils revealing upregulation of the pro-apoptotic CHOP and BiP UPR-response genes. Together, these results support specific autosomal dominant mutations in SEC61A1 causing SCN through dysregulation of the UPR.
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