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

First Author	Marom R	Year	2021
Journal	Am J Hum Genet	Volume	108
Issue	9	Pages	1710-1724
PubMed ID	34450031	Mgi Jnum	J:321261
Mgi Id	MGI:6857890	Doi	10.1016/j.ajhg.2021.08.002
Citation	Marom R, et al. (2021) COPB2 loss of function causes a coatopathy with osteoporosis and developmental delay. Am J Hum Genet 108(9):1710-1724

abstractText

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.

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

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