PUBLICATION

COPB2 loss of function causes a coatopathy with osteoporosis and developmental delay

Authors
Marom, R., Burrage, L.C., Venditti, R., Clément, A., Blanco-Sánchez, B., Jain, M., Scott, D.A., Rosenfeld, J.A., Sutton, V.R., Shinawi, M., Mirzaa, G., DeVile, C., Roberts, R., Calder, A.D., Allgrove, J., Grafe, I., Lanza, D.G., Li, X., Joeng, K.S., Lee, Y.C., Song, I.W., Sliepka, J.M., Batkovskyte, D., Washington, M., Dawson, B.C., Jin, Z., Jiang, M.M., Chen, S., Chen, Y., Tran, A.A., Emrick, L.T., Murdock, D.R., Hanchard, N.A., Zapata, G.E., Mehta, N.R., Weis, M.A., Scott, A.A., Tremp, B.A., Phillips, J.B., Wegner, J., Taylor-Miller, T., Gibbs, R.A., Muzny, D.M., Jhangiani, S.N., Hicks, J., Stottmann, R.W., Dickinson, M.E., Seavitt, J.R., Heaney, J.D., Eyre, D.R., Undiagnosed Diseases Network, Westerfield, M., De Matteis, M.A., Lee, B.
ID
ZDB-PUB-210828-48
Date
2021
Source
American journal of human genetics   108(9): 1710-1724 (Journal)
Registered Authors
Keywords
COPB2, COPI complex, coatopathy, collagen trafficking, juvenile osteoporosis
MeSH Terms
  • Animals
  • Ascorbic Acid/pharmacology
  • Bone and Bones/drug effects
  • Bone and Bones/metabolism*
  • Bone and Bones/pathology
  • Brain/diagnostic imaging
  • Brain/drug effects
  • Brain/metabolism
  • Brain/pathology
  • Child
  • Child, Preschool
  • Coat Protein Complex I/deficiency
  • Coat Protein Complex I/genetics*
  • Coatomer Protein/chemistry
  • Coatomer Protein/deficiency
  • Coatomer Protein/genetics*
  • Collagen Type I/genetics
  • Collagen Type I/metabolism
  • Developmental Disabilities/diagnostic imaging
  • Developmental Disabilities/genetics*
  • Developmental Disabilities/metabolism
  • Developmental Disabilities/pathology
  • Embryo, Nonmammalian
  • Endoplasmic Reticulum/drug effects
  • Endoplasmic Reticulum/metabolism
  • Endoplasmic Reticulum/pathology
  • Female
  • Fibroblasts/drug effects
  • Fibroblasts/metabolism
  • Fibroblasts/pathology
  • Gene Expression Regulation, Developmental
  • Golgi Apparatus
  • Haploinsufficiency
  • Humans
  • Intellectual Disability/diagnostic imaging
  • Intellectual Disability/genetics*
  • Intellectual Disability/metabolism
  • Intellectual Disability/pathology
  • Male
  • Mice
  • Osteoporosis/drug therapy
  • Osteoporosis/genetics*
  • Osteoporosis/metabolism
  • Osteoporosis/pathology
  • RNA, Small Interfering/genetics
  • RNA, Small Interfering/metabolism
  • Severity of Illness Index
  • Zebrafish
PubMed
34450031 Full text @ Am. J. Hum. Genet.
Citation
Marom, R., Burrage, L.C., Venditti, R., Clément, A., Blanco-Sánchez, B., Jain, M., Scott, D.A., Rosenfeld, J.A., Sutton, V.R., Shinawi, M., Mirzaa, G., DeVile, C., Roberts, R., Calder, A.D., Allgrove, J., Grafe, I., Lanza, D.G., Li, X., Joeng, K.S., Lee, Y.C., Song, I.W., Sliepka, J.M., Batkovskyte, D., Washington, M., Dawson, B.C., Jin, Z., Jiang, M.M., Chen, S., Chen, Y., Tran, A.A., Emrick, L.T., Murdock, D.R., Hanchard, N.A., Zapata, G.E., Mehta, N.R., Weis, M.A., Scott, A.A., Tremp, B.A., Phillips, J.B., Wegner, J., Taylor-Miller, T., Gibbs, R.A., Muzny, D.M., Jhangiani, S.N., Hicks, J., Stottmann, R.W., Dickinson, M.E., Seavitt, J.R., Heaney, J.D., Eyre, D.R., Undiagnosed Diseases Network, Westerfield, M., De Matteis, M.A., Lee, B. (2021) COPB2 loss of function causes a coatopathy with osteoporosis and developmental delay. American journal of human genetics. 108(9):1710-1724.
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. Electron microscopy of COPB2-deficient subjects' fibroblasts showed dilated endoplasmic reticulum (ER) with granular material, prominent rough ER, and vacuoles, consistent with an intracellular trafficking defect. We studied the effect of COPB2 deficiency on collagen trafficking because of the critical role of collagen secretion in bone biology. COPB2 siRNA-treated fibroblasts showed delayed collagen secretion with retention of type I collagen in the ER and Golgi and altered distribution of Golgi markers. copb2-null zebrafish embryos showed retention of type II collagen, disorganization of the ER and Golgi, and early larval lethality. Copb2+/- mice exhibited low bone mass, and consistent with the findings in human cells and zebrafish, studies in Copb2+/- mouse fibroblasts suggest ER stress and a Golgi defect. Interestingly, ascorbic acid treatment partially rescued the zebrafish developmental phenotype and the cellular phenotype in Copb2+/- mouse fibroblasts. This work identifies a form of coatopathy due to COPB2 haploinsufficiency, explores a potential therapeutic approach for this disorder, and highlights the role of the COPI complex as a regulator of skeletal homeostasis.
Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
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