%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 Ann Clin Transl Neurol %D 2018 %T Phenotypic expansion in - a common cause of intellectual disability in females. %A Wang, Xia %A Posey, Jennifer E %A Rosenfeld, Jill A %A Bacino, Carlos A %A Scaglia, Fernando %A Immken, Ladonna %A Harris, Jill M %A Hickey, Scott E %A Mosher, Theresa M %A Slavotinek, Anne %A Zhang, Jing %A Beuten, Joke %A Leduc, Magalie S %A He, Weimin %A Vetrini, Francesco %A Walkiewicz, Magdalena A %A Bi, Weimin %A Xiao, Rui %A Liu, Pengfei %A Shao, Yunru %A Gezdirici, Alper %A Gulec, Elif Y %A Jiang, Yunyun %A Darilek, Sandra A %A Hansen, Adam W %A Khayat, Michael M %A Pehlivan, Davut %A Piard, Juliette %A Donna M Muzny %A Hanchard, Neil %A Belmont, John W %A Van Maldergem, Lionel %A Richard A Gibbs %A Eldomery, Mohammad K %A Akdemir, Zeynep C %A Adesina, Adekunle M %A Chen, Shan %A Lee, Yi-Chien %A Lee, Brendan %A James R Lupski %A Eng, Christine M %A Xia, Fan %A Yang, Yaping %A Graham, Brett H %A Moretti, Paolo %X

De variants in account for 1-3% of unexplained intellectual disability (ID) cases and are amongst the most common causes of ID especially in females. Forty-seven patients (44 females, 3 males) have been described. We identified 31 additional individuals carrying 29 unique variants, including 30 postnatal individuals with complex clinical presentations of developmental delay or ID, and one fetus with abnormal ultrasound findings. Rare or novel phenotypes observed include respiratory problems, congenital heart disease, skeletal muscle mitochondrial DNA depletion, and late-onset neurologic decline. Our findings expand the spectrum of DNA variants and phenotypes associated with disorders.

%B Ann Clin Transl Neurol %V 5 %P 1277-1285 %8 2018 Oct %G eng %N 10 %1 https://www.ncbi.nlm.nih.gov/pubmed/30349862?dopt=Abstract %R 10.1002/acn3.622 %0 Journal Article %J JBMR Plus %D 2018 %T Whole-Exome Sequencing Identifies an Intronic Cryptic Splice Site in Causing Osteogenesis Imperfecta Type VI. %A Jin, Zixue %A Burrage, Lindsay C %A Jiang, Ming-Ming %A Lee, Yi-Chien %A Bertin, Terry %A Chen, Yuqing %A Tran, Alyssa %A Richard A Gibbs %A Jhangiani, Shalini %A Sutton, V Reid %A Rauch, Frank %A Lee, Brendan %A Jain, Mahim %X

The heritable disorder osteogenesis imperfecta (OI) is characterized by bone fragility and low bone mass. OI type VI is an autosomal recessive form of the disorder with moderate to severe bone fragility. OI type VI is caused by mutations in the serpin peptidase inhibitor, clade F, member 1 (), the gene coding for pigment epithelium-derived factor (PEDF). Here, we report a patient with OI type VI caused by a novel homozygous intronic variant in identified by whole-exome sequencing (WES). The mutation was not identified using a low bone mass gene panel based on next-generation sequencing. This variant creates a novel consensus splice donor site (AGGC to AGGT) in intron 4. Analysis of cDNA generated from fibroblasts revealed retention of a 32-bp intronic fragment between exons 4 and 5 in the cDNA, a result of alternative splicing from the novel splice-donor site. As a result, the aberrant insertion of this intronic fragment generated a frameshift pathogenic variant and induced nonsense-mediated decay. Furthermore, gene expression by quantitative PCR showed expression was dramatically reduced in patient fibroblasts, and PEDF level was also significantly reduced in the patient's plasma. In conclusion, we report a novel homozygous variant that generates an alternative splice-donor in intron 4 of which gives rise to severe bone fragility. The work also demonstrates clinical utility of WES analysis, and consideration of noncoding variants, in the diagnostic setting of rare bone diseases. © 2018 The Authors. is published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

%B JBMR Plus %V 2 %P 235-239 %8 2018 Jul %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/30283904?dopt=Abstract %R 10.1002/jbm4.10044