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

Kosuke Izumi; Maggie Brett; Eriko Nishi; Séverine Drunat; Ee-Shien Tan; Katsunori Fujiki; Sophie Lebon; Breana Cham; Koji Masuda; Michiko Arakawa; Adeline Jacquinet; Yusuke Yamazumi; Shu-Ting Chen; Alain Verloes; Yuki Okada; Yuki Katou; Tomohiko Nakamura; Tetsu Akiyama; Pierre Gressens; Roger Foo; Sandrine Passemard; Ene-Choo Tan; Vincent El Ghouzzi; Katsuhiko Shirahige

doi:10.1016/j.ajhg.2016.06.011

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

Kosuke Izumi, Maggie Brett, Eriko Nishi, Séverine Drunat, Ee-Shien Tan, Katsunori Fujiki, Sophie Lebon, Breana Cham, Koji Masuda, Michiko Arakawa, Adeline Jacquinet, Yusuke Yamazumi, Shu-Ting Chen, Alain Verloes, Yuki Okada, Yuki Katou, Tomohiko Nakamura, Tetsu Akiyama, Pierre Gressens, Roger FooSandrine Passemard, Ene-Choo Tan, Vincent El Ghouzzi, Katsuhiko Shirahige

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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.

Original language	English
Pages (from-to)	451–459
Journal	American Journal of Human Genetics
Volume	99
Issue number	2
Early online date	28 Jun 2016
DOIs	https://doi.org/10.1016/j.ajhg.2016.06.011
Publication status	Published - 4 Aug 2016

Keywords

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

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10.1016/j.ajhg.2016.06.011

ARCN1 Mutations Cause a_IZUMI_Accepted15June2016_GREEN AAMAccepted author manuscript, 10.5 MBLicence: CC BY-NC-ND

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Izumi, K., Brett, M., Nishi, E., Drunat, S., Tan, E.-S., Fujiki, K., Lebon, S., Cham, B., Masuda, K., Arakawa, M., Jacquinet, A., Yamazumi, Y., Chen, S.-T., Verloes, A., Okada, Y., Katou, Y., Nakamura, T., Akiyama, T., Gressens, P., ... Shirahige, K. (2016). ARCN1 Mutations Cause a Recognizable Craniofacial Syndrome Due to COPI-Mediated Transport Defects. American Journal of Human Genetics, 99(2), 451–459. https://doi.org/10.1016/j.ajhg.2016.06.011

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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.",

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author = "Kosuke Izumi and Maggie Brett and Eriko Nishi and S{\'e}verine Drunat and Ee-Shien Tan and Katsunori Fujiki and Sophie Lebon and Breana Cham and Koji Masuda and Michiko Arakawa and Adeline Jacquinet and Yusuke Yamazumi and Shu-Ting Chen and Alain Verloes and Yuki Okada and Yuki Katou and Tomohiko Nakamura and Tetsu Akiyama and Pierre Gressens and Roger Foo and Sandrine Passemard and Ene-Choo Tan and Vincent El Ghouzzi and Katsuhiko Shirahige",

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Izumi, K, Brett, M, Nishi, E, Drunat, S, Tan, E-S, Fujiki, K, Lebon, S, Cham, B, Masuda, K, Arakawa, M, Jacquinet, A, Yamazumi, Y, Chen, S-T, Verloes, A, Okada, Y, Katou, Y, Nakamura, T, Akiyama, T, Gressens, P, Foo, R, Passemard, S, Tan, E-C, El Ghouzzi, V & Shirahige, K 2016, 'ARCN1 Mutations Cause a Recognizable Craniofacial Syndrome Due to COPI-Mediated Transport Defects', American Journal of Human Genetics, vol. 99, no. 2, pp. 451–459. https://doi.org/10.1016/j.ajhg.2016.06.011

TY - JOUR

T1 - ARCN1 Mutations Cause a Recognizable Craniofacial Syndrome Due to COPI-Mediated Transport Defects

AU - Izumi, Kosuke

AU - Brett, Maggie

AU - Nishi, Eriko

AU - Drunat, Séverine

AU - Tan, Ee-Shien

AU - Fujiki, Katsunori

AU - Lebon, Sophie

AU - Cham, Breana

AU - Masuda, Koji

AU - Arakawa, Michiko

AU - Jacquinet, Adeline

AU - Yamazumi, Yusuke

AU - Chen, Shu-Ting

AU - Verloes, Alain

AU - Okada, Yuki

AU - Katou, Yuki

AU - Nakamura, Tomohiko

AU - Akiyama, Tetsu

AU - Gressens, Pierre

AU - Foo, Roger

AU - Passemard, Sandrine

AU - Tan, Ene-Choo

AU - El Ghouzzi, Vincent

AU - Shirahige, Katsuhiko

PY - 2016/8/4

Y1 - 2016/8/4

N2 - 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.

AB - 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.

KW - exome sequencing

KW - micrognathia

KW - short stature

KW - microcephalic dwarfism

KW - intracellular trafficking

KW - ER stress

KW - ARCN1-related syndrome

U2 - 10.1016/j.ajhg.2016.06.011

DO - 10.1016/j.ajhg.2016.06.011

M3 - Article

SN - 0002-9297

VL - 99

SP - 451

EP - 459

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 2

ER -

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

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Keywords

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