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

TitleCOPB2 loss of function causes a coatopathy with osteoporosis and developmental delay.
Publication TypeJournal Article
Year of Publication2021
AuthorsMarom, R, Burrage, LC, Venditti, R, Clément, A, Blanco-Sánchez, B, Jain, M, Scott, DA, Rosenfeld, JA, V Sutton, R, Shinawi, M, Mirzaa, G, DeVile, C, Roberts, R, Calder, AD, Allgrove, J, Grafe, I, Lanza, DG, Li, X, Joeng, KSang, Lee, Y-C, Song, I-W, Sliepka, JM, Batkovskyte, D, Washington, M, Dawson, BC, Jin, Z, Jiang, M-M, Chen, S, Chen, Y, Tran, AA, Emrick, LT, Murdock, DR, Hanchard, NA, Zapata, GE, Mehta, NR, Weis, MAnn, Scott, AA, Tremp, BA, Phillips, JB, Wegner, J, Taylor-Miller, T, Gibbs, RA, Muzny, DM, Jhangiani, SN, Hicks, J, Stottmann, RW, Dickinson, ME, Seavitt, JR, Heaney, JD, Eyre, DR, Westerfield, M, De Matteis, MAntonietta, Lee, B
Corporate AuthorsUndiagnosed Diseases Network
JournalAm J Hum Genet
Volume108
Issue9
Pagination1710-1724
Date Published2021 09 02
ISSN1537-6605
KeywordsAnimals, Ascorbic Acid, Bone and Bones, Brain, Child, Child, Preschool, Coat Protein Complex I, Coatomer Protein, Collagen Type I, Developmental Disabilities, Embryo, Nonmammalian, Endoplasmic Reticulum, Female, Fibroblasts, Gene Expression Regulation, Developmental, Golgi Apparatus, Haploinsufficiency, Humans, Intellectual Disability, Male, Mice, Osteoporosis, RNA, Small Interfering, Severity of Illness Index, Zebrafish
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.

DOI10.1016/j.ajhg.2021.08.002
Alternate JournalAm J Hum Genet
PubMed ID34450031
PubMed Central IDPMC8456174
Grant ListK08 DK106453 / DK / NIDDK NIH HHS / United States
T32 GM007526 / GM / NIGMS NIH HHS / United States
U54 AR068069 / AR / NIAMS NIH HHS / United States
U54 HD083092 / HD / NICHD NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States
U01 HG007709 / HG / NHGRI NIH HHS / United States
R03 DE026233 / DE / NIDCR NIH HHS / United States
U54 NS093793 / NS / NINDS NIH HHS / United States
P01 HD070394 / HD / NICHD NIH HHS / United States
K08 NS092898 / NS / NINDS NIH HHS / United States
UM1 HG006348 / HG / NHGRI NIH HHS / United States