%0 Journal Article %J Am J Hum Genet %D 2021 %T COPB2 loss of function causes a coatopathy with osteoporosis and developmental delay. %A Marom, Ronit %A Burrage, Lindsay C %A Venditti, Rossella %A Clément, Aurélie %A Blanco-Sánchez, Bernardo %A Jain, Mahim %A Scott, Daryl A %A Rosenfeld, Jill A %A Sutton, V Reid %A Shinawi, Marwan %A Mirzaa, Ghayda %A DeVile, Catherine %A Roberts, Rowenna %A Calder, Alistair D %A Allgrove, Jeremy %A Grafe, Ingo %A Lanza, Denise G %A Li, Xiaohui %A Joeng, Kyu Sang %A Lee, Yi-Chien %A Song, I-Wen %A Sliepka, Joseph M %A Batkovskyte, Dominyka %A Washington, Megan %A Dawson, Brian C %A Jin, Zixue %A Jiang, Ming-Ming %A Chen, Shan %A Chen, Yuqing %A Tran, Alyssa A %A Emrick, Lisa T %A David R Murdock %A Hanchard, Neil A %A Zapata, Gladys E %A Mehta, Nitesh R %A Weis, Mary Ann %A Scott, Abbey A %A Tremp, Brenna A %A Phillips, Jennifer B %A Wegner, Jeremy %A Taylor-Miller, Tashunka %A Richard A Gibbs %A Donna M Muzny %A Jhangiani, Shalini N %A Hicks, John %A Stottmann, Rolf W %A Dickinson, Mary E %A Seavitt, John R %A Heaney, Jason D %A Eyre, David R %A Westerfield, Monte %A De Matteis, Maria Antonietta %A Lee, Brendan %K Animals %K Ascorbic Acid %K Bone and Bones %K Brain %K Child %K Child, Preschool %K Coat Protein Complex I %K Coatomer Protein %K Collagen Type I %K Developmental Disabilities %K Embryo, Nonmammalian %K Endoplasmic Reticulum %K Female %K Fibroblasts %K Gene Expression Regulation, Developmental %K Golgi Apparatus %K Haploinsufficiency %K Humans %K Intellectual Disability %K Male %K Mice %K Osteoporosis %K RNA, Small Interfering %K Severity of Illness Index %K Zebrafish %X

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.

%B Am J Hum Genet %V 108 %P 1710-1724 %8 2021 Sep 02 %G eng %N 9 %1 https://www.ncbi.nlm.nih.gov/pubmed/34450031?dopt=Abstract %R 10.1016/j.ajhg.2021.08.002 %0 Journal Article %J Hum Mutat %D 2017 %T Heterozygous variants in ACTL6A, encoding a component of the BAF complex, are associated with intellectual disability. %A Marom, Ronit %A Jain, Mahim %A Burrage, Lindsay C %A Song, I-Wen %A Graham, Brett H %A Brown, Chester W %A Stevens, Servi J C %A Stegmann, Alexander P A %A Gunter, Andrew T %A Kaplan, Julie D %A Gavrilova, Ralitza H %A Shinawi, Marwan %A Rosenfeld, Jill A %A Bae, Yangjin %A Tran, Alyssa A %A Chen, Yuqing %A Lu, James T %A Gibbs, Richard A %A Eng, Christine %A Yang, Yaping %A Rousseau, Justine %A de Vries, Bert B A %A Campeau, Philippe M %A Lee, Brendan %K Actins %K Adolescent %K Child %K Chromatin Assembly and Disassembly %K Chromosomal Proteins, Non-Histone %K DNA Helicases %K DNA-Binding Proteins %K Exome %K Face %K Female %K Hand Deformities, Congenital %K Heterozygote %K Humans %K Intellectual Disability %K Male %K Micrognathism %K Multiprotein Complexes %K Mutation, Missense %K Nuclear Proteins %K Protein Binding %K Transcription Factors %X

Pathogenic variants in genes encoding components of the BRG1-associated factor (BAF) chromatin remodeling complex have been associated with intellectual disability syndromes. We identified heterozygous, novel variants in ACTL6A, a gene encoding a component of the BAF complex, in three subjects with varying degrees of intellectual disability. Two subjects have missense variants affecting highly conserved amino acid residues within the actin-like domain. Missense mutations in the homologous region in yeast actin were previously reported to be dominant lethal and were associated with impaired binding of the human ACTL6A to β-actin and BRG1. A third subject has a splicing variant that creates an in-frame deletion. Our findings suggest that the variants identified in our subjects may have a deleterious effect on the function of the protein by disturbing the integrity of the BAF complex. Thus, ACTL6A gene mutation analysis should be considered in patients with intellectual disability, learning disabilities, or developmental language disorder.

%B Hum Mutat %V 38 %P 1365-1371 %8 2017 Oct %G eng %N 10 %1 https://www.ncbi.nlm.nih.gov/pubmed/28649782?dopt=Abstract %R 10.1002/humu.23282