Loss of C2orf69 defines a fatal autoinflammatory syndrome in humans and zebrafish that evokes a glycogen-storage-associated mitochondriopathy.

Abstract

Human C2orf69 is an evolutionarily conserved gene whose function is unknown. Here, we report eight unrelated families from which 20 children presented with a fatal syndrome consisting of severe autoinflammation and progredient leukoencephalopathy with recurrent seizures; 12 of these subjects, whose DNA was available, segregated homozygous loss-of-function C2orf69 variants. C2ORF69 bears homology to esterase enzymes, and orthologs can be found in most eukaryotic genomes, including that of unicellular phytoplankton. We found that endogenous C2ORF69 (1) is loosely bound to mitochondria, (2) affects mitochondrial membrane potential and oxidative respiration in cultured neurons, and (3) controls the levels of the glycogen branching enzyme 1 (GBE1) consistent with a glycogen-storage-associated mitochondriopathy. We show that CRISPR-Cas9-mediated inactivation of zebrafish C2orf69 results in lethality by 8 months of age due to spontaneous epileptic seizures, which is preceded by persistent brain inflammation. Collectively, our results delineate an autoinflammatory Mendelian disorder of C2orf69 deficiency that disrupts the development/homeostasis of the immune and central nervous systems.

• Authors: Hui Hui Wong, Sze Hwee Seet, Michael Maier, Ayse Gurel, Ricardo Moreno Traspas, Cheryl Lee, Shan Zhang, Beril Talim, Abigail Y T Loh, Crystal Y Chia, Tze Shin Teoh, Danielle Sng, Jarred Rensvold, Sule Unal, Evgenia Shishkova, Ece Cepni, Fatima M Nathan, Fernanda L Sirota, Chao Liang, Nese Yarali, Pelin O Simsek-Kiper, Tadahiro Mitani, Serdar Ceylaner, Ozlem Arman-Bilir, Hamdi Mbarek, Fatma Gumruk, Stephanie Efthymiou, Deniz Uğurlu Çi Men, Danai Georgiadou, Kortessa Sotiropoulou, Henry Houlden, Franziska Paul, Davut Pehlivan, Candice Lainé, Guoliang Chai, Nur Ain Ali, Siew Chin Choo, Soh Sok Keng, Bertrand Boisson, Elanur Yılmaz, Shifeng Xue, Joshua J Coon, Thanh Thao Nguyen Ly, Naser Gilani, Dana Hasbini, Hulya Kayserili, Maha S Zaki, Robert J Isfort, Natalia Ordonez, Kornelia Tripolszki, Peter Bauer, Nima Rezaei, Simin Seyedpour, Ghamar Taj Khotaei, Charles C Bascom, Reza Maroofian, Myriam Chaabouni, Afaf Alsubhi, Wafaa Eyaid, Sedat Işıkay, Joseph G Gleeson, James R Lupski, Jean-Laurent Casanova, David J Pagliarini, Nurten A Akarsu, Sebastian Maurer-Stroh, Arda Cetinkaya, Aida Bertoli-Avella, Ajay S Mathuru, Lena Ho, Frederic A Bard, Bruno Reversade
• Journal: American journal of human genetics (Am J Hum Genet) Vol. 108 Issue 7 Pg. 1301-1317 (07 01 2021) ISSN: 1537-6605 [Electronic] United States
• PMID: 34038740 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Chemical References

• Membrane Proteins
• Glycogen

Topics

• Animals
• Biological Evolution
• CRISPR-Cas Systems
• Cell Line
• Encephalitis (genetics, mortality)
• Female
• Genes, Recessive
• Glycogen (metabolism)
• Humans
• Inflammation (genetics)
• Male
• Membrane Proteins (genetics)
• Mitochondrial Diseases (genetics, mortality)
• Pedigree
• Seizures (genetics, mortality)
• Zebrafish (genetics)