Gene expression-based, molecular pathomechanism prediction for GNE myopathy
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ABSTRACT:
PROVIDER: PRJNA376192 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Molecular impacts in the pathogenesis of GNE myopathy in model mouse muscles were well described through expression profiling of a total of 34000 genes
2017-07-01 | GSE95150 | GEO
Project description:Molecular impacts of 0.1% N-acetylcysteine treatment on GNE myopathy model mice were well described through expression profiling of a total of 34000 genes
2017-07-01 | GSE95148 | GEO
Project description:Molecular impacts of 1% N-acetylcysteine treatment on GNE myopathy model mice were well described through expression profiling of a total of 34000 genes
2017-07-01 | GSE95149 | GEO
Project description:GNE myopathy, a recessive autosomal disease caused by mutations in Glucosamine-(UDP-N-Acetyl)-2-Epimerase/N-Acetylmannosamine Kinase (GNE), is characterized by deficient sialic acid (SA) production and the formation of rimmed vacuoles. Similar to other autophagic vacuolar myopathies, defective autophagy has been identified as a causative factor in GNE myopathy. However, the molecular mechanism underlying this defective autophagy has not been fully determined. Through transcriptome analysis of two GNE myoblast models derived from human pluripotent stem cells (hPSCs), several gene sets associated with autophagy were identified as pathogenic gene signatures of GNE myopathy. This prediction, along with subsequent biochemical validation using GNE knockout in C2C12 myoblasts (KO cells), revealed that high production of extracellular matrix promoted focal adhesion and subsequent activation of the AKT-mTORC axis, leading to inhibitory phosphorylation of ULK1 and impeding autophagy initiation in KO cells. Notably, transcriptome-based drug screening for candidates that inversely correlate with the pathogenic gene signature identified copanlisib, an FDA-approved PI3K inhibitor, as a potential therapeutic candidate for GNE myopathy. As predicted, copanlisib enhanced autophagy by inhibiting mTOR-dependent ULK1 phosphorylation. These results suggest that copanlisib could be a feasible therapeutic option for patients with GNE myopathy.
2026-05-15 | GSE278862 | GEO
Project description:GNE myopathy, a recessive autosomal disease caused by mutations in Glucosamine-(UDP-N-Acetyl)-2-Epimerase/N-Acetylmannosamine Kinase (GNE), is characterized by deficient sialic acid (SA) production and the formation of rimmed vacuoles. Similar to other autophagic vacuolar myopathies, defective autophagy has been identified as a causative factor in GNE myopathy. However, the molecular mechanism underlying this defective autophagy has not been fully determined. Through transcriptome analysis of two GNE myoblast models derived from human pluripotent stem cells (hPSCs), several gene sets associated with autophagy were identified as pathogenic gene signatures of GNE myopathy. This prediction, along with subsequent biochemical validation using GNE knockout in C2C12 myoblasts (KO cells), revealed that high production of extracellular matrix promoted focal adhesion and subsequent activation of the AKT-mTORC axis, leading to inhibitory phosphorylation of ULK1 and impeding autophagy initiation in KO cells. Notably, transcriptome-based drug screening for candidates that inversely correlate with the pathogenic gene signature identified copanlisib, an FDA-approved PI3K inhibitor, as a potential therapeutic candidate for GNE myopathy. As predicted, copanlisib enhanced autophagy by inhibiting mTOR-dependent ULK1 phosphorylation. These results suggest that copanlisib could be a feasible therapeutic option for patients with GNE myopathy.
2026-06-30 | GSE300471 | GEO
Project description:Gene expression-based, molecular pathomechanism prediction for GNE myopathy I
| PRJNA376193 | ENA
Project description:Gene expression-based, molecular pathomechanism prediction for GNE myopathy III
| PRJNA376194 | ENA
Project description:Gene expression-based, molecular pathomechanism prediction for GNE myopathy II
| PRJNA376195 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below.
2017-07-01 | GSE95151 | GEO
Project description:GNE myopathy is an adult onset neuromuscular disorder characterized by slowly progressive distal and proximal muscle weakness, caused by missense recessive mutations in the GNE gene. Although the encoded bifunctional enzyme is well known as the limiting factor in the biosynthesis of sialic acid, no clear mechanisms have been recognized to account for the muscle atrophic pathology, and novel functions for GNE have been hypothesized. Two major issues impair studies on this protein. First, the expression of the GNE protein is minimal in humans and mice muscles and there is no reliable antibody to follow up endogenous expression. Second, no reliable animal model is available for the disease and cellular models from GNE myopathy patients' muscle cells (expressing the mutated protein) are less informative than expected. In order to broaden our knowledge on GNE functions in muscle, we have taken advantage of the CRISPR/Cas9 method for genome editing to first, add a tag to the endogenous Gne gene in mouse, allowing the determination of the spatiotemporal expression of the protein in the organism using well established and reliable antibodies against the specific tag. In addition we have generated a Gne knock out murine muscle cell lineage to identify the events resulting from the total lack of the protein. A thorough multi-omics analysis of both systems including transcriptomics, proteomics, phosphoproteomics and ubiquitination, unraveled novel pathways for Gne, in particular its involvement in cell cycle control and in the DNA damage/repair pathway. The elucidation of fundamental mechanisms of Gne in normal muscle may contribute to the identification of the disrupted functions in GNE myopathy, thus, to the definition of novel biomarkers and possible therapeutic targets for this disease.
2023-03-10 | PXD033985 | Pride