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

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.

SUBMITTER: Marom R 

PROVIDER: S-EPMC8456174 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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

Marom Ronit R   Burrage Lindsay C LC   Venditti Rossella R   Clément Aurélie A   Blanco-Sánchez Bernardo B   Jain Mahim M   Scott Daryl A DA   Rosenfeld Jill A JA   Sutton V Reid VR   Shinawi Marwan M   Mirzaa Ghayda G   DeVile Catherine C   Roberts Rowenna R   Calder Alistair D AD   Allgrove Jeremy J   Grafe Ingo I   Lanza Denise G DG   Li Xiaohui X   Joeng Kyu Sang KS   Lee Yi-Chien YC   Song I-Wen IW   Sliepka Joseph M JM   Batkovskyte Dominyka D   Washington Megan M   Dawson Brian C BC   Jin Zixue Z   Jiang Ming-Ming MM   Chen Shan S   Chen Yuqing Y   Tran Alyssa A AA   Emrick Lisa T LT   Murdock David R DR   Hanchard Neil A NA   Zapata Gladys E GE   Mehta Nitesh R NR   Weis Mary Ann MA   Scott Abbey A AA   Tremp Brenna A BA   Phillips Jennifer B JB   Wegner Jeremy J   Taylor-Miller Tashunka T   Gibbs Richard A RA   Muzny Donna M DM   Jhangiani Shalini N SN   Hicks John J   Stottmann Rolf W RW   Dickinson Mary E ME   Seavitt John R JR   Heaney Jason D JD   Eyre David R DR   Westerfield Monte M   De Matteis Maria Antonietta MA   Lee Brendan B  

American journal of human genetics 20210826 9

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. Elect  ...[more]

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