title: ARCN1 Mutations Cause a Recognizable Craniofacial Syndrome Due to COPI-Mediated Transport Defects.
abstract: 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.
authors.affiliation: Research Center for Epigenetic Disease, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo 113-0032, Japan; Division of Medical Genetics, Nagano Children's Hospital, Azumino 399-8205, Japan; Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. Electronic address: izumik1@email.chop.edu.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Izumi
authors.affiliation: KK Research Centre, KK Women's and Children's Hospital, Singapore 229899, Singapore.
authors.forename: Maggie
authors.initials: M
authors.lastname: Brett
authors.affiliation: Division of Medical Genetics, Nagano Children's Hospital, Azumino 399-8205, Japan; Department of Medical Genetics, Shinshu University Graduate School of Medicine, Matsumoto 390-0802, Japan; Life Science Research Center, Nagano Children's Hospital, Azumino 399-8205, Japan.
authors.forename: Eriko
authors.initials: E
authors.lastname: Nishi
authors.affiliation: INSERM UMR1141, Hôpital Robert Debré, Paris 75019, France; Département de Génétique, Hôpital Robert Debré, Paris 75019, France.
authors.forename: Séverine
authors.initials: S
authors.lastname: Drunat
authors.affiliation: Genetics Service, Department of Paediatrics, KK Women's and Children's Hospital, Singapore 229899, Singapore.
authors.forename: Ee-Shien
authors.initials: ES
authors.lastname: Tan
authors.affiliation: Research Center for Epigenetic Disease, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo 113-0032, Japan.
authors.forename: Katsunori
authors.initials: K
authors.lastname: Fujiki
authors.affiliation: INSERM UMR1141, Hôpital Robert Debré, Paris 75019, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Lebon
authors.affiliation: Genetics Service, Department of Paediatrics, KK Women's and Children's Hospital, Singapore 229899, Singapore.
authors.forename: Breana
authors.initials: B
authors.lastname: Cham
authors.affiliation: Research Center for Epigenetic Disease, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo 113-0032, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Masuda
authors.affiliation: Division of Medical Genetics, Nagano Children's Hospital, Azumino 399-8205, Japan.
authors.forename: Michiko
authors.initials: M
authors.lastname: Arakawa
authors.affiliation: Département de Génétique, Centre Hospitalier Universitaire et Université de Liège, Liège 4000, Belgium.
authors.forename: Adeline
authors.initials: A
authors.lastname: Jacquinet
authors.affiliation: Laboratory of Molecular and Genetic Information, Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo 113-0032, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Yamazumi
authors.affiliation: Research Center for Epigenetic Disease, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo 113-0032, Japan.
authors.forename: Shu-Ting
authors.initials: ST
authors.lastname: Chen
authors.affiliation: INSERM UMR1141, Hôpital Robert Debré, Paris 75019, France; Département de Génétique, Hôpital Robert Debré, Paris 75019, France; Université Paris Diderot (Paris 7), Hôpital Robert Debré, Paris 75019, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Verloes
authors.affiliation: Laboratory of Pathology and Development, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo 113-0032, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Okada
authors.affiliation: Research Center for Epigenetic Disease, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo 113-0032, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Katou
authors.affiliation: Life Science Research Center, Nagano Children's Hospital, Azumino 399-8205, Japan.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Nakamura
authors.affiliation: Laboratory of Molecular and Genetic Information, Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo 113-0032, Japan.
authors.forename: Tetsu
authors.initials: T
authors.lastname: Akiyama
authors.affiliation: INSERM UMR1141, Hôpital Robert Debré, Paris 75019, France; Université Paris Diderot (Paris 7), Hôpital Robert Debré, Paris 75019, France; The Centre for the Developing Brain, King's College London, St. Thomas' Hospital, London SE1-7EH, UK.
authors.forename: Pierre
authors.initials: P
authors.lastname: Gressens
authors.affiliation: Genetics Service, Department of Paediatrics, KK Women's and Children's Hospital, Singapore 229899, Singapore; Genome Institute of Singapore, Singapore 138672, Singapore.
authors.forename: Roger
authors.initials: R
authors.lastname: Foo
authors.affiliation: INSERM UMR1141, Hôpital Robert Debré, Paris 75019, France; Département de Génétique, Hôpital Robert Debré, Paris 75019, France; Université Paris Diderot (Paris 7), Hôpital Robert Debré, Paris 75019, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Passemard
authors.affiliation: KK Research Centre, KK Women's and Children's Hospital, Singapore 229899, Singapore; Paediatrics ACP, SingHealth Duke-NUS Medical School, Singapore 169857, Singapore.
authors.forename: Ene-Choo
authors.initials: EC
authors.lastname: Tan
authors.affiliation: INSERM UMR1141, Hôpital Robert Debré, Paris 75019, France; Université Paris Diderot (Paris 7), Hôpital Robert Debré, Paris 75019, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: El Ghouzzi
authors.affiliation: Research Center for Epigenetic Disease, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo 113-0032, Japan; CREST, Japan Science and Technology Agency, Kawaguchi, 332-0012, Japan.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Shirahige
mesh_terms: D000328:Adult; D020755:Coat Protein Complex I / Q000378:metabolism*; D020756:Coatomer Protein / Q000235:genetics* / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D019465:Craniofacial Abnormalities / Q000235:genetics*; D059865:Endoplasmic Reticulum Stress; D006579:Heterozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D013577:Syndrome
chemical_list: D020755:Coat Protein Complex I; D020756:Coatomer Protein; D003094:Collagen
keywords: ARCN1-related syndrome; ER stress; exome sequencing; intracellular trafficking; microcephalic dwarfism; micrognathia; short stature