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<jats:title>Abstract</jats:title><jats:p>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 <jats:italic>COPB2</jats:italic>, 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 <jats:italic>COPB2</jats:italic> deficiency on skeletal development in mice and zebrafish. <jats:italic>Copb2</jats:italic><jats:sup><jats:italic>+/−</jats:italic></jats:sup> mice showed low bone mass and decreased bone strength. In zebrafish, larvae carrying a <jats:italic>copb2</jats:italic> heterozygous frameshift variant showed delayed mineralization. <jats:italic>copb2</jats:italic>-null embryos showed endoplasmic reticulum (ER) and Golgi disorganization, and embryonic lethality. <jats:italic>COPB2</jats:italic> 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 <jats:italic>COPB2</jats:italic> 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 <jats:italic>COPB2</jats:italic> deficiency.</jats:p>

Original publication

DOI

10.1101/2020.09.14.297234

Type

Journal article

Publisher

Cold Spring Harbor Laboratory

Publication Date

16/09/2020