B3GALT6 mutations trigger sequential molecular events leading to compromised connective tissue biomechanics in Ehlers-Danlos syndrome
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PROVIDER: PRJNA1009412 | ENA |
REPOSITORIES: ENA
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Project description:Ehlers-Danlos syndromes (EDS) comprise a genetically and clinically heterogenous group of rare diseases that cause severe, often fatal, damage to connective tissue. The molecular basis of EDS implicates defects in extracellular matrix components, including various fibrillar collagens and glycosaminoglycans (GAGs). However, the precise pathogenic mechanisms behind EDS remain elusive. Here, we have implemented a multi-tiered approach to demonstrate the functional impact of B3GALT6 mutations on biochemical and developmental processes, ultimately leading to the spondylodysplastic subtype of EDS (spEDS), characterized by severe musculoskeletal symptoms. We show that the loss of function of β1,3-galactosyltransferase 6 (β3GalT6) is partially compensated by β1,3-glucuronosyltransferase 3 (GlcAT-I), the next enzyme in the GAG biosynthetic pathway. In addition, results from transcriptomics, collagen analysis and biophysical experiments revealed that impaired collagen maturation, including defective glycosylation of collagen XII, contributes to altered tissue structure and biomechanics, the hallmarks of spEDS. Our findings unravel a new pathogenic mechanism of spEDS, and bring us one step closer to therapeutic strategies, including cell and tissue engineering.
2025-07-10 | GSE241724 | GEO
Project description:Ehlers-Danlos SYndrome (SEDSY) was performed compared to 4 control healty samples with the aim to identify dysregulated genes and pathways and to use this information to propose potential drugs that could be repurposed for the treatment, based on computational approaches to drug repositioning.In summary, this comprehensive study expands our understanding of the molecular basis of Ehlers-Danlos syndrome, particularly relating to COL3A1 mutations. The integration of transcriptomic analysis, pathway studies, and drug repurposing strategies provides a robust framework for identifying potential therapeutic strategies for EDS.
2025-06-10 | GSE270199 | GEO
Project description:Multicellular spheroid from 10 Ehlers-Danlos SYndrome (EDS) patients were used to perform transcritomic experiment. These were compared to 4 control healty samples with the aim to identify dysregulated genes and pathways and to use this information to propose potential drugs that could be repurposed for the treatment, based on computational approaches to drug repositioning.In summary, this comprehensive study expands our understanding of the molecular basis of Ehlers-Danlos syndrome, particularly relating to COL3A1 mutations. The integration of transcriptomic analysis, pathway studies, and drug repurposing strategies provides a robust framework for identifying potential therapeutic strategies for EDS.
2025-06-10 | GSE270410 | GEO
Project description:10 Ehlers-Danlos SYndrome (EDS) patients
| PRJNA1164743 | ENA
Project description:Classic Ehlers Danlos syndrome (cEDS) is one of the most common genetic disorders of the connective tissue and musculoskeletal system characterized by mutations in genes encoding for type V collagen. Defects in wound healing constitute one of the most common and debilitating symptoms in individuals with cEDS but currently, no therapeutic strategies exist to attenuate wound healing defects in cEDS. We create a new murine model of cEDS, that remarkably phenocopies wound healing defects in human cEDS. Using this model, we show that an abnormal extracellular matrix (ECM) characterized by fibrillar disarray, altered mechanical properties and decreased collagen deposition contribute to the wound healing defect in cEDS. The cEDS animals exhibit decreased expression of epidermal genes and increased inflammation consistent with the human phenotype. We show that integrin expression is altered in wounds of cEDS animals and small molecule modulators of mechanosensitive integrin signaling attenuate wound healing defects. Finally, we demonstrate that rescuing extracellular matrix defects by injecting wild type fibroblasts into wounds of cEDS animals significantly enhances epidermal gene expression, decreases inflammation, augments wound closure and rescues defective wound repair. Taken together, these observations suggest that modulation of the extracellular matrix in Ehlers-Danlos syndrome either with small molecule inhibitors of mechanosensitive integrin signaling, or direct injection of wild type fibroblasts into the wound bed may have therapeutic potential for enhancing wound healing in cEDS.
2024-08-01 | GSE264169 | GEO
Project description:Vascular Ehlers-Danlos syndrome is a rare inherited disorder caused by genetic variants in type III collagen. Its prognosis is especially hampered by unpredictable arterial ruptures and there is no therapeutic consensus. We created a knock-in Col3a1+/G182R mouse model and performed a complete genetic, molecular and biochemical characterization. Several therapeutic strategies were also tested. Col3a1+/G182R mice showed a spontaneous mortality caused by thoracic aortic rupture that recapitulates the vascular Ehlers-Danlos syndrome with a lower survival rate in males, thin non-inflammatory arteries and an altered arterial collagen. Transcriptomic analysis of aortas showed upregulation of genes related to inflammation and cell stress response. Compared to water, survival rate of Col3a1+/G182R mice was not affected by beta-blockers (propranolol or celiprolol). Two other vasodilating anti-hypertensive agents (hydralazine, amlodipine) gave opposite results on aortic rupture and mortality rate. There was a spectacular beneficial effect of losartan, reversed by the cessation of its administration, and a marked deleterious effect of exogenous angiotensin II. These results suggest that blockade of the renin angiotensin system should be tested as a first-line medical therapy in patients with vascular Ehlers-Danlos syndrome.
2022-02-16 | GSE196753 | GEO
Project description:Periodontal Ehlers–Danlos syndrome (pEDS) is a rare, distinct hereditary disorder characterized by early onset periodontal destruction, tissue fragility and joint hypermobility. pEDS is caused by mutant variants of C1R (and C1S) genes, which encode the C1s (and C1s) subunits of the first component of the classical complement pathway. Abberant serine protease activation will result in C4 cleavage and local complement cascade activation, as well as other possible consequences. Although multiple studies have investigated the genetic variant analysis of pEDS, the transcriptome profiles of pEDS remain unknown. To better understand the pathomechanism underlying the clinical manifestation of pEDS and to identify novel molecular targets that may expand treatment strategies, our study performed transcriptome profiling by RNA sequencing of patient-derived monocytes from 2 pEDS patients and 3 normal controls. Genes related to periodontal host defense, inflammatory response, skin disease and vascular development were significantly enriched. Furthermore, we identified genes that may be involved in the pathogenesis of periodontal destruction and pretibial pigmentation of pEDS. Overall, our study presents the first pEDS transcriptomics data, revealing distinct molecular features in monocytes of periodontal Ehlers–Danlos syndrome, and serves as a tool to better understand the disease.
2021-12-16 | GSE190786 | GEO
Project description:Gene expression profiling of cultured skin fibroblasts obtained from patients affected with classical Ehlers Danlos syndrome (cEDS) Transcriptome-wide expression profiling using the Affymetrix Gene 1.0 ST platform comparing the gene expression pattern of cultured skin fibroblasts from 4 cEDS patients with those of 9 healthy individuals
2019-01-21 | GSE117680 | GEO
Project description:Analysis of gene expression profiling of cultured skin fibroblasts obtained from patients affected with vascular Ehlers Danlos syndrome (vEDS) Transcriptome-wide expression profiling using the Affymetrix Gene 1.0 ST platform comparing the gene expression pattern of cultured skin fibroblasts derived from three patients with vEDS with those of nine healthy individuals
2018-01-03 | GSE102042 | GEO
Project description:Vascular Ehlers-Danlos syndrome (vEDS) is a severe connective tissue disorder caused by dominant mutations in the COL3A1 gene, which encodes type III collagen (COLLIII). COLLIII is primarily found in blood vessels and hollow organs, and its deficiency causes fragile soft connective tissues, with life-threatening arterial and organ ruptures. There are currently no targeted therapies available. Although disease results from COLLIII misfolding caused by triple helix structure disruption, the underlying pathomechanisms are largely unknown. To address this knowledge gap, we conducted a comprehensive transcriptome analysis using RNA-seq on a large cohort of dermal fibroblasts from vEDS patients and healthy donors. Our investigation revealed an intricate interplay between proteostasis abnormalities, inefficient endoplasmic reticulum (ER) stress response, and compromised autophagy, which may significantly impact the molecular pathology. We reported the first comprehensive map of complex gene expression networks, which may provide significant molecular insights into intricate interactions within cellular signaling pathways. the current RNA-seq data not only confirm these initial findings but also provide convincing evidence that ineffective proteostasis, unbalanced ER homeostasis, and compromised autophagy could substantially impact the molecular pathology driving the disease. aken together, or findings suggest that the accumulation of these misfolded aggregates can impair critical cellular functions such as ER proteostasis, adaptative responses to counteract ER stress (UPR and ERAD pathways), autophagy, mTOR pathway, and lysosome function. Perturbation of these key biological processes can have an impact on a range of cell activities, including differentiation, proliferation, and apoptosis, all of which are associated with the pathophysiology of vEDS. This work was supported by Fondazione Telethon and the “Associazione con Giacomo contro vEDS”, (Grant number: GSA21F001, Seed Grant Fall 2021 vEDS) to Nicola Chiarelli.
2023-10-13 | GSE239914 | GEO