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

Autor:	Marom R; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA., Burrage LC; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA., Venditti R; Telethon Institute of Genetics and Medicine, Naples 80078, Italy., Clément A; Institute of Neuroscience, University of Oregon, Eugene, OR 97403, USA., Blanco-Sánchez B; Institute of Neuroscience, University of Oregon, Eugene, OR 97403, USA., Jain M; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA., Scott DA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA; Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA., Rosenfeld JA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA., Sutton VR; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA., Shinawi M; Department of Pediatrics, Division of Genetics and Genomic Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA., Mirzaa G; Center for Integrative Brain Research, Seattle Children's Research Institute, and Department of Pediatrics, University of Washington, and Brotman Baty Institute for Precision Medicine, Seattle, WA 98105, USA., DeVile C; Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK., Roberts R; Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK., Calder AD; Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK., Allgrove J; Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK., Grafe I; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA., Lanza DG; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA., Li X; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA., Joeng KS; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA., Lee YC; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA., Song IW; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA., Sliepka JM; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA., Batkovskyte D; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA., Washington M; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA., Dawson BC; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA., Jin Z; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA., Jiang MM; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA., Chen S; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA., Chen Y; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA., Tran AA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA., Emrick LT; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA; Department of Pediatrics, Section of Neurology and Developmental Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA., Murdock DR; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA., Hanchard NA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA; Laboratory for Translational Genomics, ARS/USDA Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX 77030, USA., Zapata GE; Laboratory for Translational Genomics, ARS/USDA Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX 77030, USA., Mehta NR; Laboratory for Translational Genomics, ARS/USDA Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX 77030, USA., Weis MA; Department of Orthopaedics and Sports Medicine, University of Washington, Seattle, WA 98195, USA., Scott AA; Division of Genetic Medicine, Seattle Children's Hospital, Seattle, WA 98105, USA., Tremp BA; Institute of Neuroscience, University of Oregon, Eugene, OR 97403, USA., Phillips JB; Institute of Neuroscience, University of Oregon, Eugene, OR 97403, USA., Wegner J; Institute of Neuroscience, University of Oregon, Eugene, OR 97403, USA., Taylor-Miller T; Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK., Gibbs RA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA., Muzny DM; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA., Jhangiani SN; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA., Hicks J; Texas Children's Hospital, Houston, TX 77030, USA; Department of Pathology, Texas Children's Hospital, and Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA., Stottmann RW; Division of Human Genetics, and Division of Developmental Biology, and Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA., Dickinson ME; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA., Seavitt JR; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA., Heaney JD; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA., Eyre DR; Department of Orthopaedics and Sports Medicine, University of Washington, Seattle, WA 98195, USA., Westerfield M; Institute of Neuroscience, University of Oregon, Eugene, OR 97403, USA., De Matteis MA; Telethon Institute of Genetics and Medicine, Naples 80078, Italy; Department of Molecular Medicine and Medical Biotechnology, University of Napoli Federico II, Naples 80078, Italy., Lee B; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA. Electronic address: blee@bcm.edu.
Jazyk:	angličtina
Zdroj:	American journal of human genetics [Am J Hum Genet] 2021 Sep 02; Vol. 108 (9), pp. 1710-1724. Date of Electronic Publication: 2021 Aug 26.
DOI:	10.1016/j.ajhg.2021.08.002
Abstrakt:	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. Competing Interests: Declaration of interests The Department of Molecular and Human Genetics at Baylor College of Medicine receives financial support from Baylor Genetics. Dr. Brendan Lee serves on the Board of Directors of Baylor Genetics and chairs its Scientific Advisory Board but receives no personal income from these positions. (Copyright © 2021 American Society of Human Genetics. All rights reserved.)
Databáze:	MEDLINE
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