The Capillary Morphogenesis Gene 2 Triggers the Intracellular Hallmarks of Collagen VI-Related Muscular Dystrophy

Castroflorio, Enrico; Berná, Ana Joaquina Pérez; López-Márquez, Arístides; Badosa, Carmen; Loza-Álvarez, Pablo; Roldán, Mónica; Jiménez‐Mallebrera, Cecilia

doi:10.3390/ijms23147651

Cited by 5 publications

(5 citation statements)

References 74 publications

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“…Another potential link between collagen VI deficiency and the effect of EVs on cell motility is hinted at by our recent work which demonstrates a direct functional link between collagen VI, the Capillary Morphogenesis Gene 2 Protein, CMG2, receptor and the endocytic pathway. We showed an increased number of endosomes in fibroblasts from patients with COL6-RD which was associated with increased phosphorylation of CMG2 which in turn modulates the actin cytoskeleton via RhoA and talins 6 although this would require further signalling studies.…”

Section: Discussionmentioning

confidence: 85%

“…In skeletal muscle, collagen VI is released by endomysial fibroblasts and once in the extracellular matrix interacts with other extracellular proteins and components of the muscle basement membrane connecting at the structural and signaling levels the muscle cell with the surrounding connective tissue 4 . We and others have described that, mutations in collagen VI genes leading to collagen VI defects result in a global phenotypic change of the fibroblasts which is reflected in very significant changes in their gene expression profile and specific functions such as adhesion 5 as well as organelles structure organization 6 .…”

Section: Introductionmentioning

confidence: 99%

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Proteomic and functional characterisation of extracellular vesicles from collagen VI deficient human fibroblasts reveals a role in cell motility

Badosa,

Roldán,

Fernández-Irigoyen

et al. 2023

Sci Rep

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Extracellular vesicles (EVs) are key mediators of cell-to-cell communication. Their content reflects the state of diseased cells representing a window into disease progression. Collagen-VI Related Muscular Dystrophy (COL6-RD) is a multi-systemic disease involving different cell types. The role of EVs in this disease has not been explored. We compared by quantitative proteomics the protein cargo of EVs released from fibroblasts from patients with COL6-RD and controls. Isolated EVs contained a significant proportion of the most frequently reported proteins in EVs according to Exocarta and Vesiclepedia. We identified 67 differentially abundant proteins associated with vesicle transport and exocytosis, actin remodelling and the cytoskeleton, hemostasis and oxidative stress. Treatment of control fibroblasts with EVs from either patient or healthy fibroblasts altered significantly the motility of cells on a cell migration assay highlighting the functional relevance of EVs. In parallel, we analysed the secretome from the same cells and found a distinctly different set of 48 differentially abundant proteins related to extracellular matrix organisation and remodelling, growth factor response, RNA metabolism and the proteasome. The EVs and secretome sets of proteins only shared two identifiers indicating that the sorting of proteins towards EVs or the secretory pathway is tightly regulated for different functions.

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Section: Discussionmentioning

confidence: 85%

Section: Introductionmentioning

confidence: 99%

Proteomic and functional characterisation of extracellular vesicles from collagen VI deficient human fibroblasts reveals a role in cell motility

Badosa,

Roldán,

Fernández-Irigoyen

et al. 2023

Sci Rep

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“…Capillary morphogenesis gene 2 (CMG2) is a transmembrane surface protein also expressed by muscle cells, which mediates the intracellular degradation of collagen VI. An impairment in the CMG2 activity has been documented in COL6-RM skin fibroblasts [66]. It is noteworthy that patients carrying CMG2 mutations accumulate abnormal amounts of collagen VI, leading to nodule formation [67].…”

Section: Discussionmentioning

confidence: 99%

New Clinical and Immunofluorescence Data of Collagen VI-Related Myopathy: A Single Center Cohort of 69 Patients

Merlini,

Sabatelli,

Gualandi

et al. 2023

IJMS

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Pathogenetic mechanism recognition and proof-of-concept clinical trials were performed in our patients affected by collagen VI-related myopathies. This study, which included 69 patients, aimed to identify innovative clinical data to better design future trials. Among the patients, 33 had Bethlem myopathy (BM), 24 had Ullrich congenital muscular dystrophy (UCMD), 7 had an intermediate phenotype (INTM), and five had myosclerosis myopathy (MM). We obtained data on muscle strength, the degree of contracture, immunofluorescence, and genetics. In our BM group, only one third had a knee extension strength greater than 50% of the predicted value, while only one in ten showed similar retention of elbow flexion. These findings should be considered when recruiting BM patients for future trials. All the MM patients had axial and limb contractures that limited both the flexion and extension ranges of motion, and a limitation in mouth opening. The immunofluorescence analysis of collagen VI in 55 biopsies from 37 patients confirmed the correlation between collagen VI defects and the severity of the clinical phenotype. However, biopsies from the same patient or from patients with the same mutation taken at different times showed a progressive increase in protein expression with age. The new finding of the time-dependent modulation of collagen VI expression should be considered in genetic correction trials.

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“…This gene is crucial to standard physiological processes. Some studies demonstrate that CMG2 regulates endosomal and lysosomal function as a collagen VI receptor 36 . Furthermore, ANTXR2 correlates with the low-density lipoprotein receptor-associated Protein 6 (LRP6) gene, which is a coreceptor for Wnt signaling.…”

Section: Discussionmentioning

confidence: 99%

Identification and verification of genes associated with hypoxia microenvironment in Alzheimer’s disease

Yuan,

Feng,

Zhao

et al. 2023

Sci Rep

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As the incidence of Alzheimer's disease (AD) increases year by year, more people begin to study this disease. In recent years, many studies on reactive oxygen species (ROS), neuroinflammation, autophagy, and other fields have confirmed that hypoxia is closely related to AD. However, no researchers have used bioinformatics methods to study the relationship between AD and hypoxia. Therefore, our study aimed to screen the role of hypoxia-related genes in AD and clarify their diagnostic significance. A total of 7681 differentially expressed genes (DEGs) were identified in GSE33000 by differential expression analysis and cluster analysis. Weighted gene co-expression network analysis (WGCNA) was used to detect 9 modules and 205 hub genes with high correlation coefficients. Next, machine learning algorithms were applied to 205 hub genes and four key genes were selected. Through the verification of external dataset and quantitative real-time PCR (qRT-PCR), the AD diagnostic model was established by ANTXR2, BDNF and NFKBIA. The bioinformatics analysis results suggest that hypoxia-related genes may increase the risk of AD. However, more in-depth studies are still needed to investigate their association, this article would guide the insights and directions for further research.

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The Capillary Morphogenesis Gene 2 Triggers the Intracellular Hallmarks of Collagen VI-Related Muscular Dystrophy

Cited by 5 publications

References 74 publications

Proteomic and functional characterisation of extracellular vesicles from collagen VI deficient human fibroblasts reveals a role in cell motility

Proteomic and functional characterisation of extracellular vesicles from collagen VI deficient human fibroblasts reveals a role in cell motility

New Clinical and Immunofluorescence Data of Collagen VI-Related Myopathy: A Single Center Cohort of 69 Patients

Identification and verification of genes associated with hypoxia microenvironment in Alzheimer’s disease

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