Year: 2020
Type: preprint
Abstract: Coatomer complexes function in the sorting and trafficking of proteins between subcellular organelles. Pathogenic variants in coatomer subunits or associated factors have been reported in multi-systemic disorders, i.e., coatopathies, that can affect the skeletal and central nervous systems. We have identified loss-of-function variants in COPB2 , a component of the coatomer complex I (COPI), in individuals presenting with osteoporosis, fractures and developmental delay of variable severity. Because the role of COPB2 in bone has not been characterized, we studied the effect of COPB2 deficiency on skeletal development in mice and zebrafish. Copb2 +/− mice showed low bone mass and decreased bone strength. In zebrafish, larvae carrying a copb2 heterozygous frameshift variant showed delayed mineralization. copb2 -null embryos showed endoplasmic reticulum (ER) and Golgi disorganization, and embryonic lethality. COPB2 siRNA-treated fibroblasts showed delayed collagen trafficking with retention of type I collagen in the ER and Golgi, and altered distribution of Golgi markers. Our data suggest that COPB2 haploinsufficiency leads to disruption of intracellular collagen trafficking and osteoporosis, which may improve with ascorbic acid supplementation. This work highlights the role of COPI complex as a critical regulator of bone mass and identifies a new form of coatopathy due to COPB2 deficiency.
Authors: Ronit Marom, Lindsay C. Burrage, Aurélie Clément, Bernardo Blanco-Sánchez, Rossella Venditti, Mahim Jain, Ingo Grafe, Daryl A. Scott, Jill A. Rosenfeld, V. Reid Sutton, Marwan Shinawi, Ghayda Mirzaa, Catherine DeVile, Rowenna Roberts, Alistair D Calder, Jeremy Allgrove, Denise G. Lanza, Xiaohui Li, Kyu Sang Joeng, Yi-Chien Lee, I-Wen Song, Joseph M. Sliepka, Dominyka Batkovskyte, Zixue Jin, Brian C. Dawson, Shan Chen, Yuqing Chen, Ming-Ming Jiang, Elda M. Munivez, Alyssa A. Tran, Lisa T. Emrick, David R. Murdock, Neil A. Hanchard, Gladys E. Zapata, Nitesh R. Mehta, Mary Ann Weis, Cole Kuzawa, Abbey Scott, Brenna A. Tremp, Jennifer B. Phillips, Jeremy Wegner, Tashunka Taylor-Miller, Richard A. Gibbs, Donna M. Muzny, Shalini N. Jhangiani, Rolf W. Stottmann, Mary E. Dickinson, John R. Seavitt, Jason D. Heaney, David R. Eyre, Catherine G. Ambrose, Undiagnosed Diseases Network Monte Westerfield, Maria Antonella De Matteis, Brendan Lee
Institutions: Baylor College of Medicine, Texas Children's Hospital, University of Oregon, Telethon Institute Of Genetics And Medicine, Washington University in St. Louis, University of Washington, Brotman Baty Institute, Seattle Children's Research Institute, Great Ormond Street Hospital for Children NHS Foundation Trust, Children's Nutrition Research Center at Baylor College of Medicine, The University of Texas Health Science Center at Houston, Seattle Children's Hospital, Cincinnati Children's Hospital Medical Center, University of Naples Federico II
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: green
Funders: U.S. Department of Agriculture, Burroughs Wellcome Fund, Associazione Italiana per la Ricerca sul Cancro, National Institutes of Health, Intellectual and Developmental Disabilities Research Center, National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institute of Dental and Craniofacial Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, H2020 European Research Council
Awards: G1081015277, G1269453416, G255694563, G2788838719, G2843249294, G2844676560, G2866955307, G3402682446, G3804157208, G4011631407, G4102661714, G4444814008, G4507691384, Genes and pathways underlying brain overgrowth and focal cortical malformations, G4634093248, G5039737598, Collagen Cross-linking in Skeletal Aging and Disease, G5373717429, G5950577451, G6524013220, G664261826, Pathogenesis of Novel Forms of Osteogenesis Imperfecta, G8181538647, G8548656140, Systems Biology of Membrane Trafficking, G8811310105, G9000074939, G9000086497, G9000096724, G9000111579, G9000145427, G9000175825, G9000213352, G9000237818, G9000293998, Medical Genetics Research Fellowship Program
OpenAlex ID: W3084766547