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. Epub 2016 Jul 28.


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.

Publication types

  • Case Reports

MeSH terms

  • Adult
  • Coat Protein Complex I / metabolism*
  • Coatomer Protein / genetics*
  • Coatomer Protein / metabolism
  • Collagen / metabolism
  • Craniofacial Abnormalities / genetics*
  • Endoplasmic Reticulum Stress
  • Heterozygote
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Mutation*
  • Syndrome


  • Coat Protein Complex I
  • Coatomer Protein
  • Collagen