PT  - JOURNAL ARTICLE
AU  - Ronit Marom
AU  - Lindsay C. Burrage
AU  - Aurélie Clément
AU  - Bernardo Blanco-Sánchez
AU  - Rossella Venditti
AU  - Mahim Jain
AU  - Ingo Grafe
AU  - Daryl A. Scott
AU  - Jill A. Rosenfeld
AU  - V. Reid Sutton
AU  - Marwan Shinawi
AU  - Ghayda Mirzaa
AU  - Catherine DeVile
AU  - Rowenna Roberts
AU  - Alistair D Calder
AU  - Jeremy Allgrove
AU  - Denise G. Lanza
AU  - Xiaohui Li
AU  - Kyu Sang Joeng
AU  - Yi-Chien Lee
AU  - I-Wen Song
AU  - Joseph M. Sliepka
AU  - Dominyka Batkovskyte
AU  - Zixue Jin
AU  - Brian C. Dawson
AU  - Shan Chen
AU  - Yuqing Chen
AU  - Ming-Ming Jiang
AU  - Elda M. Munivez
AU  - Alyssa A. Tran
AU  - Lisa T. Emrick
AU  - David R. Murdock
AU  - Neil A. Hanchard
AU  - Gladys E. Zapata
AU  - Nitesh R. Mehta
AU  - Mary Ann Weis
AU  - Cole Kuzawa
AU  - Abbey Scott
AU  - Brenna A. Tremp
AU  - Jennifer B. Phillips
AU  - Jeremy Wegner
AU  - Tashunka Taylor-Miller
AU  - Richard A. Gibbs
AU  - Donna M. Muzny
AU  - Shalini N. Jhangiani
AU  - Rolf W. Stottmann
AU  - Mary E. Dickinson
AU  - John R. Seavitt
AU  - Jason D. Heaney
AU  - David R. Eyre
AU  - Catherine G. Ambrose
AU  - Undiagnosed Diseases Network Monte Westerfield
AU  - Maria Antonella De Matteis
AU  - Brendan Lee
TI  - <em>COPB2</em> haploinsufficiency causes a coatopathy with osteoporosis and developmental delay
AID  - 10.1101/2020.09.14.297234
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.09.14.297234
4099  - http://biorxiv.org/content/early/2020/09/15/2020.09.14.297234.short
4100  - http://biorxiv.org/content/early/2020/09/15/2020.09.14.297234.full
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. Because the role of COPB2 in bone has not been characterized, we studied the effect of COPB2 deficiency on skeletal development in mice and zebrafish. Copb2+/− mice showed low bone mass and decreased bone strength. In zebrafish, larvae carrying a copb2 heterozygous frameshift variant showed delayed mineralization. copb2-null embryos showed endoplasmic reticulum (ER) and Golgi disorganization, and embryonic lethality. COPB2 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 COPB2 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 COPB2 deficiency.Competing Interest StatementThe authors have declared no competing interest.