Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1166338 | ENA |
REPOSITORIES: ENA
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Project description:Myxomatous valve disease is the most common form of heart valve disease leading to morbidity and mortality worldwide. It is primarily associated with inherited connective tissue disorders caused by genetic variants in extracellular matrix genes such as Marfan syndrome. Mice with Fibrillin 1 gene variant Fbn1 C1039G/+ recapitulate histopathological features of Marfan syndrome. However, the cell heterogeneity and changes of gene expression at single cell level in Marfan syndrome valves are completed unknown.
2024-10-15 | GSE261874 | GEO
Project description:Fibrillin-1, an extracellular matrix (ECM) protein encoded by FBN1 gene, serves as the microfibril scaffold crucial for elastic fiber formation and homeostasis in pliable tissue such as the skin. Besides causing Marfan syndrome, some mutations in FBN1 result in scleroderma, marked by hardened and thicker skin which limits joint mobility. Here, we analyzed the secreted protein profile (secretome) of fibroblast prepared from the Fbn1G234D/G234D mouse model carrying a corresponding variant of FBN1 in the hybrid-1 domain, which was identified in a patient with familial aortic dissection.
2025-04-11 | PXD052580 | JPOST Repository
Project description:Analysis of mouse Adamts6 and Adamts10 mutant embryos, lacking these homologous secreted metalloproteases individually and in combination, along with in vitro analysis of microfibrils, measurement of ADAMTS6-fibrillin affinities and N-terminomics determination of ADAMTS6-cleaved sites, demonstrates a transcriptionally adapted system for fibrillin-2 proteolysis that contributes to postnatal fibrillin-1 dominance. The lack of ADAMTS6, alone and in combination with ADAMTS10 led to excess fibrillin-2 in perichondrium, with impaired skeletal development. Although ADAMTS6 cleaves fibrillin-1 and fibrillin-2 as well as fibronectin, which provides the initial scaffold for microfibril assembly, primacy of the protease-substrate relationship between ADAMTS6 and fibrillin-2 was unequivocally established by reversal of these defects in Adamts6-/- embryos by genetic reduction of Fbn2, but not Fbn1.
2022-05-20 | PXD027096 | Pride
Project description:Fibrillin-1 (FBN1) is the major component of extracellular matrix microfibrils, which are required for proper development of elastic tissues including heart and lung. Through protein-protein interactions with latent TGF-beta binding protein 1 (LTBP1), microfibrils assist regulation of TGF-beta signaling. Mutations within the 47 epidermal growth factor-like (EGF) repeats of FBN1 cause autosomal dominant disorders including Marfan Syndrome that disrupt TGF-beta signaling. We recently identified 2 novel protein O-glucosyltransferases, Protein O-glucosyltransferase 2 (POGLUT2) and Protein O-glucosyltransferase 3 (POGLUT3), that modify a few EGF repeats on Notch. Here, using mass spectral analysis, we show that POGLUT2 and POGLUT3 also modify over half of the EGF repeats on FBN1, fibrillin-2 (FBN2), and LTBP1. While most sites are modified by both enzymes, some sites show a preference for either POGLUT2 or POGLUT3. POGLUT2 and POGLUT3 are homologs of POGLUT1, which stabilizes Notch proteins by addition of O-glucose to Notch EGF repeats. Like POGLUT1, POGLUT2 and 3 can discern a folded versus unfolded EGF repeat, suggesting POGLUT2 and 3 are involved in a protein folding pathway. In vitro secretion assays using recombinant FBN1 revealed reduced FBN1 secretion in POGLUT2 knockout, POGLUT3 knockout, and POGLUT2 and 3 double knockout HEK293T cells compared to wild type. These results illustrate that POGLUT2 and 3 function together to O-glycosylate protein targets, and that these modifications play a role in secretion of target proteins.
2021-08-06 | PXD025725 | Pride
Project description:RNA-Seq of fibrillin 1 (Fbn1) tight-skin (Tsk) mice
| PRJNA737339 | ENA
Project description:Duchenne muscular dystrophy (DMD) involves progressive muscle degeneration associated with calcium dysregulation, but the mechanisms linking extracellular matrix (ECM) integrity to calcium homeostasis remain unclear. We investigated whether MUA-3, a fibrillin-related ECM protein in Caenorhabditis elegans, contributes to calcium regulation in dystrophic muscle. Using fluorescent calcium imaging in transgenic worms expressing muscle-specific GCaMP2, we found that downregulating mua-3 selectively elevated resting calcium levels in healthy muscle but had no effect in dystrophic (dys-1) muscle, suggesting impaired MUA-3 function in dystrophy. Despite altered calcium dynamics, mua-3 downregulation did not affect locomotor function. In human dystrophic myoblasts, we observed significantly elevated sarcoplasmic calcium levels concurrent with substantial downregulation of fibrillin genes FBN1/FBN2. These findings demonstrate that fibrillin-related proteins regulate calcium homeostasis across species, suggesting that ECM integrity directly contributes to cellular calcium control in muscle. This work identifies a conserved mechanism linking extracellular matrix stability to intracellular calcium regulation and suggests that targeting ECM-calcium coupling may offer new therapeutic approaches for muscular dystrophy.
2025-09-01 | GSE299627 | GEO
Project description:We generated a novel genetic mouse model of fatal aortic dissection by introducing a pathogenic variant of Fbn1 (Fbn1G234D/G234D), identified in a patient with familial aortic dissection, into mice using the CRISPR/Cas9 system. To investigate the cellular heterogeneity underlying the progression of aortic dissection, we performed single cell RNA sequencing on aortic tissues obtained from Fbn1G234D/G234D (AD) and wild-type mice (WT).
2025-05-30 | GSE294679 | GEO
Project description:Fibrillins, which are extensively O-glucosylated by POGLUT2 and 3, are crucial for development and cardiopulmonary function. Using primary dermal fibroblasts derived from our POGLUT 2 and 3 double knockout mouse model combined with proteomics analyses, we show that loss of O-glucose modifications on fibrillin causes compositional changes in the extracellular environment compared to controls. Notably, a 30-50% reduction in the abundance of FBN1 and 2 was found in media samples whereas an 85% reduction was found in the extracellular matrix. Other proteins in the extracellular matrix also exhibited changes in abundance in the double knockout samples compared to wild type, but it is still unclear if these changes are simply secondary to the significant reduction in fibrillins.
2024-06-10 | PXD043730 | Pride
Project description:We used microarrays to characterize the global changes in gene expression within the ascending aorta of mice due to conditional disruption of TGF-M-NM-2 signaling in smooth muscle and/or due to heterozygous fibrillin-1 mutation. Myh11-CreERT2.Tgfbr2f/f (abbreviated as Cre.Tgfbr2) mice were cross-bred to Fbn1C1039G/+ (abbreviated as Fbn1C/+) mice and treated with vehicle or tamoxifen for 5 d starting at 4 wk of age to generate 4 groups of animals: 1) Cre.Tgfbr2-Veh: controls with intact TGF-M-NM-2 signaling and wild-type fibrillin-1 expression; 2) Cre.Tgfbr2-Tmx: conditional disruption of Tgfbr2 in smooth muscle with wild-type fibrillin-1 expression; 3) Fbn1C1039G.Cre.Tgfbr2-Veh: heterozygous expression of mutant fibrillin-1 with intact TGF-M-NM-2 signaling; and 4) Fbn1C1039G.Cre.Tgfbr2-Tmx: conditional disruption of Tgfbr2 in smooth muscle with heterozygous expression of mutant fibrillin-1. The animals were euthanized at 6 weeks of age and their ascending aortas (from above the coronary arteries to the first arch branch) were collected and total RNA was extracted.
2013-05-31 | E-GEOD-36778 | biostudies-arrayexpress