TY - JOUR
T1 - COPB2 loss of function causes a coatopathy with osteoporosis and developmental delay
AU - Undiagnosed Diseases Network
AU - Marom, Ronit
AU - Burrage, Lindsay C.
AU - Venditti, Rossella
AU - Clément, Aurélie
AU - Blanco-Sánchez, Bernardo
AU - Jain, Mahim
AU - Scott, Daryl A.
AU - Rosenfeld, Jill A.
AU - Sutton, V. Reid
AU - Shinawi, Marwan
AU - Mirzaa, Ghayda
AU - DeVile, Catherine
AU - Roberts, Rowenna
AU - Calder, Alistair D.
AU - Allgrove, Jeremy
AU - Grafe, Ingo
AU - Lanza, Denise G.
AU - Li, Xiaohui
AU - Joeng, Kyu Sang
AU - Lee, Yi Chien
AU - Song, I. Wen
AU - Sliepka, Joseph M.
AU - Batkovskyte, Dominyka
AU - Washington, Megan
AU - Dawson, Brian C.
AU - Jin, Zixue
AU - Jiang, Ming Ming
AU - Chen, Shan
AU - Chen, Yuqing
AU - Tran, Alyssa A.
AU - Emrick, Lisa T.
AU - Murdock, David R.
AU - Hanchard, Neil A.
AU - Zapata, Gladys E.
AU - Mehta, Nitesh R.
AU - Weis, Mary Ann
AU - Scott, Abbey A.
AU - Tremp, Brenna A.
AU - Phillips, Jennifer B.
AU - Wegner, Jeremy
AU - Taylor-Miller, Tashunka
AU - Gibbs, Richard A.
AU - Muzny, Donna M.
AU - Jhangiani, Shalini N.
AU - Hicks, John
AU - Stottmann, Rolf W.
AU - Dickinson, Mary E.
AU - Seavitt, John R.
AU - Heaney, Jason D.
AU - Eyre, David R.
AU - Westerfield, Monte
AU - De Matteis, Maria Antonietta
AU - Lee, Brendan
N1 - Publisher Copyright:
© 2021 American Society of Human Genetics
PY - 2021/9/2
Y1 - 2021/9/2
N2 - 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.
AB - 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.
KW - COPB2
KW - COPI complex
KW - coatopathy
KW - collagen trafficking
KW - juvenile osteoporosis
UR - http://www.scopus.com/inward/record.url?scp=85114035191&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2021.08.002
DO - 10.1016/j.ajhg.2021.08.002
M3 - Article
C2 - 34450031
AN - SCOPUS:85114035191
SN - 0002-9297
VL - 108
SP - 1710
EP - 1724
JO - American journal of human genetics
JF - American journal of human genetics
IS - 9
ER -