PIEZO1 loss of function compound heterozygous mutation in the rare congenital human disorder Prune Belly Syndrome
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PROVIDER: PRJNA1041491 | ENA |
REPOSITORIES: ENA
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Project description:PIEZO1 loss of function compound heterozygous mutation in the rare congenital human disorder Prune Belly Syndrome
| PRJNA1041492 | ENA
Project description:PIEZO1 is a mechanically-activated ion channel that contributes to flow sensing in vascular endothelium. Moreover, deletion of endothelial PIEZO1 was recently found to suppress activation of Notch1 target genes in hepatic microvascular endothelium. Here, because of the liver’s dominant role in lipid regulation, we set out to test the novel hypothesis that endothelial PIEZO1 regulates hepatic lipid homeostasis. We performed bulk RNA sequencing on PIEZO1-deleted mice exposed to chow and high fat diets. Our transcriptomics analysis reveal unexpected relevance to lipid and glucose homeostasis.
2024-06-29 | E-MTAB-9996 | biostudies-arrayexpress
Project description:Mutations in the RYR1 gene are the most common cause of human congenital myopathies and patients with recessive mutations are severely affected and characteristically display ptosis and/or ophthalmoplegia. In order to gain insight into the mechanism leading to extraocular muscle involvement, we investigated the biochemical, structural and physiological properties of eye muscles from mouse models we created knocked-in for RYR1 mutations. Ex vivo force production in extraocular muscles from compound heterozygous RyR1p.Q1970fsX16+p.A4329D mutant mice was significantly reduced compared to that observed in WT. The decrease in muscle force was also accompanied by approximately a 40% reduction in RyR1 protein content, a decrease in electrically evoked calcium transients, disorganization of the muscle ultrastructure and a decrease in the number of calcium release units. Unexpectedly, the superfast and ocular-muscle specific myosin heavy chain-EO isoform was almost undetectable in RyR1p.Q1970fsX16+p.A4329D mutant mice. The results of this study show for the first time that the extraocular muscle phenotype caused by compound heterozygous RYR1 mutations is due to reduced content of ryanodine and dihydropyridine receptors, the presence of fewer calcium release units and associated mitochondria as well as disorganization of myofiber structure. Additionally, the presence of the two mutations leads to the almost complete absence of the extraocular muscle-specific isoform of myosin heavy chain.
2023-03-15 | PXD016879 | Pride
Project description:The propeller-shaped blades of the PIEZO1 and PIEZO2 ion channels partition into the plasma membrane and respond to indentation or stretching of the lipid bilayer, thus converting mechanical forces into signals that can be interpreted by cells, in the form of calcium flux and changes in membrane potential. While PIEZO channels participate in diverse physiological processes, from sensing the shear stress of blood flow in the vasculature to detecting a light touch on the surface of the skin, the molecular details that enable these mechanosensors to tune their responses over a vast dynamic range of forces remain largely uncharacterized. To survey the molecular landscape surrounding PIEZO channels at the cell surface, we employed a mass spectrometry-based proteomic approach to capture and identify extracellularly exposed proteins in the vicinity of PIEZO1. This PIEZO1-proximal interactome was enriched in surface proteins localized to cell junctions and signaling hubs within the plasma membrane. Functional screening of these interaction candidates by calcium imaging and electrophysiology in an overexpression system identified the adhesion molecule CADM1/SynCAM that slows the inactivation kinetics of PIEZO1 with little effect on PIEZO2. Conversely, we found that CADM1 knockdown accelerates inactivation of endogenous PIEZO1 in Neuro-2a cells. Systematic deletion of CADM1 domains indicate that the transmembrane region is critical for the observed effects on PIEZO1, suggesting that modulation of inactivation is mediated by interactions in or near the lipid bilayer.
2024-10-30 | PXD054618 | Pride
Project description:In gastric cancer (GC), PIEZO1 was suggested to promote cell migration by interacting with Trefoil factor family 1 (TFF1) and serve as a therapeutic target against invasion and metastasis. In addition, PIEZO1 demonstrates abundant expression in most GC cell lines and primary samples and highly-expressed PIEZO1 is associated with poor disease-specific survival. As Yoda1 is known to be an agonist of PIEZO1, we try to explore the PIEZO1 function in GC by Yoda1 treatment.
2023-12-08 | GSE228691 | GEO
Project description:Piezo1 is a mechanosensitive ion channel that has gained recognition for its role in regulating diverse physiological processes. However, the influence of Piezo1 in inflammatory disease, including infection and tumor-immunity, is not well-studied. We postulated that Piezo1 links physical forces to immune regulation in myeloid cells. We discovered signal transduction via Piezo1 in myeloid cells and established this channel as the primary sensor of mechanical stress in these cells. Global inhibition of Piezo1 was protective against both cancer and septic shock and resulted in a diminution in suppressive myeloid cells. Moreover, deletion of Piezo1 in myeloid cells protected against cancer and increased survival in poly-microbial sepsis. Mechanistically, we show that mechanical stimulation promotes Piezo1-dependent myeloid cell expansion by suppressing Rb. We further show Piezo1-mediated silencing of Rb is regulated via upregulation of HDAC2. Collectively, our work uncovers Piezo1 as a targetable immune checkpoint that drives immune-suppressive myelopoiesis in cancer and infectious disease.
2020-08-21 | GSE155340 | GEO
Project description:Achalasia is rare in the pediatric population and should prompt clinicians to consider genetic disorders associated with this condition. While AAA syndrome (also known as Allgrove or Triple A syndrome) is commonly considered, GMPPA-congenital disorder of glycosylation (CDG) should also be in the differential diagnosis. We report a 9-month-old female born to nonconsanguineous parents with achalasia and alacrima found to have two novel compound heterozygous variants in the GMPPA gene associated with GMPPA-CDG. This rare disorder is commonly associated with developmental delay and intellectual disability. We discuss management of this disorder including the importance of confirming a genetic diagnosis and summarize reported cases.
| S-EPMC9283290 | biostudies-literature
Project description:In gastric cancer (GC), PIEZO1 was suggested to promote cell migration by interacting with Trefoil factor family 1 (TFF1) and serve as a therapeutic target against invasion and metastasis. In addition, PIEZO1 demonstrates abundant expression in most GC cell lines and primary samples and highly-expressed PIEZO1 is associated with poor disease-specific survival. Thus, we try to explore the PIEZO1 function in GC by knocking down assay.
2023-12-08 | GSE228690 | GEO
Project description:The mechanisms by which physical forces regulate cells to determine complexities of vascular structure and function are enigmatic. Here we show the role the ion channel subunit Piezo1 (FAM38A). Disruption of mouse Piezo1 gene disturbed vascular development and was embryonic lethal within days of the heart beating to cause blood flow. Importance of Piezo channels as sensors of blood flow was indicated by Piezo1 dependence of shear stress-evoked ionic current and calcium influx in endothelial cells and the ability of exogenous Piezo1 to confer shear stress sensitivity on cells that otherwise lacked. Downstream of this calcium influx was proteoase activity and spatial organization of endothelial cells to the polarity of the applied force. Without Piezo1, normal endothelial cell organization was lacking. The data suggest Piezo1 channels as pivotal integrators of vascular architacture with physiological mechanical force.
2014-08-08 | PXD001099 | Pride
Project description:Mechanical force is a fundamental regulator of bone development and homeostasis. Mechanosensitive osteocytes are the most abundant bone cells that form interconnected dendrites to respond to mechanical stimuli and interact with the bone-forming osteoblasts and the bone-remodeling osteoclasts. However, the molecular mechanisms underlying osteocyte maturation and dendrite formation remain unclear. By generating a Piezo1 "knock-out" osteocyte cell line, we identified a key role of Piezo1-mediated mechanotransduction in osteocyte differentiation. QRT-PCR analysis revealed delayed osteocyte differentiation in the Piezo1 KO cells relative to WT cells. By performing bulk RNA sequencing of WT and Piezo1 KO OCY454 cells at early (D1), intermediate (D14), and late (D28) stages of differentiation allowed for the identification of key signaling pathways in driving normal osteocyte dfiferentiation, as well as those regulated by Piezo1 mechanotransduction.
2024-09-20 | GSE277264 | GEO