1. ARCN1 Mutations Cause a Recognizable Craniofacial Syndrome Due to COPI-Mediated Transport Defects
- Author
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Michiko Arakawa, Katsuhiko Shirahige, Ee-Shien Tan, Maggie Brett, Séverine Drunat, Sophie Lebon, Tetsu Akiyama, Breana Cham, Eriko Nishi, Yuki Okada, Alain Verloes, Shu-Ting Chen, Sandrine Passemard, Roger Foo, Vincent El Ghouzzi, Adeline Jacquinet, Kosuke Izumi, Koji Masuda, Tomohiko Nakamura, Yusuke Yamazumi, Pierre Gressens, Katsunori Fujiki, Yuki Katou, Ene-Choo Tan, Department of Pediatrics (Perelman School of Medicine), University of Pennsylvania [Philadelphia], Marfan Research Group, Westmead Hospital [Sydney], Département de génétique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Geological Survey of Japan (GSJ), National Institute of Advanced Industrial Science and Technology (AIST), Research Center for Epigenetic Disease, The University of Tokyo (UTokyo), Physiopathologie, conséquences fonctionnelles et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 (UPD7)-IFR2-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Génétique Clinique [CHU Debré], AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Universitaire de Liège (CHU-Liège), Département de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), and KK Women’s and Children’s Hospital (KKH)
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0301 basic medicine ,Adult ,Male ,micrognathia ,Heterozygote ,intracellular trafficking ,[SDV]Life Sciences [q-bio] ,Cellular homeostasis ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,Clathrin ,Coatomer Protein ,Coat Protein Complex I ,Craniofacial Abnormalities ,03 medical and health sciences ,symbols.namesake ,0302 clinical medicine ,Report ,Genetics ,Humans ,Genetics(clinical) ,COPII ,Genetics (clinical) ,ComputingMilieux_MISCELLANEOUS ,[SDV.GEN]Life Sciences [q-bio]/Genetics ,biology ,Endoplasmic reticulum ,microcephalic dwarfism ,Infant, Newborn ,Infant ,ARCN1-related syndrome ,COPI ,Syndrome ,Golgi apparatus ,Endoplasmic Reticulum Stress ,short stature ,030104 developmental biology ,[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics ,Coatomer ,Mutation ,Unfolded protein response ,biology.protein ,symbols ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Collagen ,ER stress ,exome sequencing ,030217 neurology & neurosurgery - Abstract
International audience; Cellular homeostasis is maintained by the highly organized cooperation of intracellular trafficking systems, including COPI, COPII, and clathrin complexes. COPI is a coatomer protein complex responsible for intracellular protein transport between the endoplasmic reticulum and the Golgi apparatus. The importance of such intracellular transport mechanisms is underscored by the various disorders, including skeletal disorders such as cranio-lenticulo-sutural dysplasia and osteogenesis imperfect, caused by mutations in the COPII coatomer complex. In this article, we report a clinically recognizable craniofacial disorder characterized by facial dysmorphisms, severe micrognathia, rhizomelic shortening, microcephalic dwarfism, and mild developmental delay due to loss-of-function heterozygous mutations in ARCN1, which encodes the coatomer subunit delta of COPI. ARCN1 mutant cell lines were revealed to have endoplasmic reticulum stress, suggesting the involvement of ER stress response in the pathogenesis of this disorder. Given that ARCN1 deficiency causes defective type I collagen transport, reduction of collagen secretion represents the likely mechanism underlying the skeletal phenotype that characterizes this condition. Our findings demonstrate the importance of COPI-mediated transport in human development, including skeletogenesis and brain growth.
- Published
- 2016
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