ARCN1 Mutations Cause a Recognizable Craniofacial Syndrome Due to COPI-Mediated Transport Defects

Am J Hum Genet. 2016 Aug 4;99(2):451-9. doi: 10.1016/j.ajhg.2016.06.011.

Kosuke Izumi ¹, Maggie Brett ², Eriko Nishi ³, Séverine Drunat ⁴, Ee-Shien Tan ⁵, Katsunori Fujiki ⁶, Sophie Lebon ⁷, Breana Cham ⁵, Koji Masuda ⁶, Michiko Arakawa ⁸, Adeline Jacquinet ⁹, Yusuke Yamazumi ¹⁰, Shu-Ting Chen ⁶, Alain Verloes ¹¹, Yuki Okada ¹², Yuki Katou ⁶, Tomohiko Nakamura ¹³, Tetsu Akiyama ¹⁰, Pierre Gressens ¹⁴, Roger Foo ¹⁵, Sandrine Passemard ¹¹, Ene-Choo Tan ¹⁶, Vincent El Ghouzzi ¹⁷, Katsuhiko Shirahige ¹⁸

Affiliations

1 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: [email protected].
2 KK Research Centre, KK Women's and Children's Hospital, Singapore 229899, Singapore.
3 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.
4 INSERM UMR1141, Hôpital Robert Debré, Paris 75019, France; Département de Génétique, Hôpital Robert Debré, Paris 75019, France.
5 Genetics Service, Department of Paediatrics, KK Women's and Children's Hospital, Singapore 229899, Singapore.
6 Research Center for Epigenetic Disease, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo 113-0032, Japan.
7 INSERM UMR1141, Hôpital Robert Debré, Paris 75019, France.
8 Division of Medical Genetics, Nagano Children's Hospital, Azumino 399-8205, Japan.
9 Département de Génétique, Centre Hospitalier Universitaire et Université de Liège, Liège 4000, Belgium.
10 Laboratory of Molecular and Genetic Information, Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo 113-0032, Japan.
11 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.
12 Laboratory of Pathology and Development, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo 113-0032, Japan.
13 Life Science Research Center, Nagano Children's Hospital, Azumino 399-8205, Japan.
14 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.
15 Genetics Service, Department of Paediatrics, KK Women's and Children's Hospital, Singapore 229899, Singapore; Genome Institute of Singapore, Singapore 138672, Singapore.
16 KK Research Centre, KK Women's and Children's Hospital, Singapore 229899, Singapore; Paediatrics ACP, SingHealth Duke-NUS Medical School, Singapore 169857, Singapore.
17 INSERM UMR1141, Hôpital Robert Debré, Paris 75019, France; Université Paris Diderot (Paris 7), Hôpital Robert Debré, Paris 75019, France.
18 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.

PMID: 27476655 DOI: 10.1016/j.ajhg.2016.06.011

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.

Keywords

ARCN1-related syndrome; ER stress; exome sequencing; intracellular trafficking; microcephalic dwarfism; micrognathia; short stature.

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