The Capillary Morphogenesis Gene 2 Triggers the Intracellular Hallmarks of Collagen VI-Related Muscular Dystrophy
Por:
Castroflorio E, Pérez Berná AJ, López-Marquez A, Badosa-Gallego MC, Loza-Alvarez P, Roldan-Molina M and Jimenez-Mallebrera C
Publicada:
1 jul 2022
Ahead of Print:
11 jul 2022
Resumen:
Collagen VI-related disorders (COL6-RD) represent a severe form of congenital disease for which there is no treatment. Dominant-negative pathogenic variants in the genes encoding alpha chains of collagen VI are the main cause of COL6-RD. Here we report that patient-derived fibroblasts carrying a common single nucleotide variant mutation are unable to build the extracellular collagen VI network. This correlates with the intracellular accumulation of endosomes and lysosomes triggered by the increased phosphorylation of the collagen VI receptor CMG2. Notably, using a CRISPR-Cas9 gene-editing tool to silence the dominant-negative mutation in patients' cells, we rescued the normal extracellular collagen VI network, CMG2 phosphorylation levels, and the accumulation of endosomes and lysosomes. Our findings reveal an unanticipated role of CMG2 in regulating endosomal and lysosomal homeostasis and suggest that mutated collagen VI dysregulates the intracellular environment in fibroblasts in collagen VI-related muscular dystrophy.
Filiaciones:
Castroflorio E:
ICFO-The Institute of Photonic Sciences, The Barcelona Institute of Science and Technology, 08860 Castelldefels, Spain
Pérez Berná AJ:
ALBA Synchrotron Light Source, 08290 Cerdanyola del Vallès, Spain
López-Marquez A:
Laboratorio de Investigación Aplicada en Enfermedades Neuromusculares, Unidad de Patología Neuromuscular, Servicio de Neuropediatría, Institut de Recerca Sant Joan de Déu, 08950 Esplugues de Llobregat, Spain
Institut de Recerca Sant Joan de Déu, 08950 Esplugues de Llobregat, Spain
Centro de Investigaciones Biomédicas en Red de Enfermedades Rara (CIBERER), 28029 Madrid, Spain
Badosa-Gallego MC:
Laboratorio de Investigación Aplicada en Enfermedades Neuromusculares, Unidad de Patología Neuromuscular, Servicio de Neuropediatría, Institut de Recerca Sant Joan de Déu, 08950 Esplugues de Llobregat, Spain
Institut de Recerca Sant Joan de Déu, 08950 Esplugues de Llobregat, Spain
Loza-Alvarez P:
ICFO-The Institute of Photonic Sciences, The Barcelona Institute of Science and Technology, 08860 Castelldefels, Spain
Roldan-Molina M:
Institut de Recerca Sant Joan de Déu, 08950 Esplugues de Llobregat, Spain
Unitat de Microscòpia Confocal i Imatge Cellular, Servei de Medicina Genètica i Molecular, Institut Pediàtric de Malaties Rares (IPER), Hospital Sant Joan de Déu, 08950 Esplugues de Llobregat, Spain
Jimenez-Mallebrera C:
Laboratorio de Investigación Aplicada en Enfermedades Neuromusculares, Unidad de Patología Neuromuscular, Servicio de Neuropediatría, Institut de Recerca Sant Joan de Déu, 08950 Esplugues de Llobregat, Spain
Institut de Recerca Sant Joan de Déu, 08950 Esplugues de Llobregat, Spain
Centro de Investigaciones Biomédicas en Red de Enfermedades Rara (CIBERER), 28029 Madrid, Spain
Department of Genetics, University of Barcelona, 08028 Barcelona, Spain
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