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

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 Çi̇men; 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

doi:10.1016/j.ajhg.2021.05.003

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

Journal article

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

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, …

American journal of human genetics, Vol.108(7), pp.1301-1317

01/07/2021

DOI: https://doi.org/10.1016/j.ajhg.2021.05.003

PMID: 34038740

Abstract

C2ORF69, mitochondriopathy, inflammation, GBE1, encephalopathy, zebrafish, Elbracht-Işikay syndrome, lipase, glycogen, Mendelian genetics

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.

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Title: Loss of C2orf69 defines a fatal autoinflammatory syndrome in humans and zebrafish that evokes a glycogen-storage-associated mitochondriopathy
Creators - without role: Hui Hui Wong - Institute of Molecular and Cell Biology, A∗STAR, Biopolis, Singapore 138673, Singapore
Sze Hwee Seet - Institute of Molecular and Cell Biology
Michael Maier - Genome Institute of Singapore
Ayse Gurel - Hacettepe University
Ricardo Moreno Traspas - Genome Institute of Singapore
Cheryl Lee - Institute of Molecular and Cell Biology
Shan Zhang - Hacettepe University
Beril Talim - Hacettepe University
Abigail Y.T. Loh - Institute of Molecular and Cell Biology, A∗STAR, Biopolis, Singapore 138673, Singapore
Crystal Y. Chia - Genome Institute of Singapore
Tze Shin Teoh - Genome Institute of Singapore
Danielle Sng - Agency for Science, Technology and Research
Jarred Rensvold - Morgridge Institute for Research
Sule Unal - Hacettepe University
Evgenia Shishkova - University of Wisconsin–Madison
Ece Cepni - Koç University
Fatima M. Nathan - Yale-NUS College
Fernanda L. Sirota - Bioinformatics Institute
Chao Liang - Hacettepe University
Nese Yarali - Ministry of Health
Pelin O. Simsek-Kiper - Hacettepe University
Tadahiro Mitani - Baylor College of Medicine
Serdar Ceylaner - Intergen
Ozlem Arman-Bilir - Ministry of Health
Hamdi Mbarek - Qatar Foundation
Fatma Gumruk - Hacettepe University
Stephanie Efthymiou - St George's, University of London
Deniz Uğurlu Çi̇men - Koç University
Danai Georgiadou - Genome Institute of Singapore
Kortessa Sotiropoulou - Institute of Molecular and Cell Biology
Henry Houlden - National Hospital for Neurology and Neurosurgery
Franziska Paul - Institute of Molecular and Cell Biology
Davut Pehlivan - Baylor College of Medicine
Candice Lainé - Imagine Institute for Genetic Diseases
Guoliang Chai - University of California, San Diego
Nur Ain Ali - Genome Institute of Singapore
Siew Chin Choo - Genome Institute of Singapore
Soh Sok Keng - Institute of Molecular and Cell Biology
Bertrand Boisson - Rockefeller University
Elanur Yılmaz - Koç University
Shifeng Xue - Institute of Molecular and Cell Biology
Joshua J. Coon - Morgridge Institute for Research
Thanh Thao Nguyen Ly - Institute of Molecular and Cell Biology, A∗STAR, Biopolis, Singapore 138673, Singapore
Naser Gilani - Farabi Medical Laboratory, Erbil, Iraq
Dana Hasbini - Rafik Hariri University Hospital
Hulya Kayserili - Koç University
Maha S. Zaki - National Research Centre
Robert J. Isfort - Procter & Gamble
Natalia Ordonez - Centogene
Kornelia Tripolszki - Centogene
Peter Bauer - Centogene
Nima Rezaei - Children's Medical Center
Simin Seyedpour - Laboratoire d’analyses spécialisé en Génétique, Tunis 1082, Tunisia
Ghamar Taj Khotaei - Tehran University of Medical Sciences
Charles C. Bascom - Procter & Gamble
Reza Maroofian - St George's, University of London
Myriam Chaabouni - Laboratoire d’analyses spécialisé en Génétique, Tunis 1082, Tunisia
Afaf Alsubhi - King Saud bin Abdulaziz University for Health Sciences
Wafaa Eyaid - King Abdulaziz Medical City
Sedat Işıkay - Department of Pediatrics, Division of Neurology, University of Gaziantep, School of Medicine, Gaziantep 27310, Turkey
Joseph G. Gleeson - University of California, San Diego
James R. Lupski - Baylor College of Medicine
Jean-Laurent Casanova - Rockefeller University
David J. Pagliarini - University of Wisconsin–Madison
Nurten A. Akarsu - Hacettepe University
Sebastian Maurer-Stroh - Agency for Science, Technology and Research
Arda Cetinkaya - Hacettepe University
Aida Bertoli-Avella - Centogene
Ajay S. Mathuru - Agency for Science, Technology and Research
Lena Ho - Institute of Molecular and Cell Biology
Frederic A. Bard - Institute of Molecular and Cell Biology
Bruno Reversade - Institute of Molecular and Cell Biology
Publication Details: American journal of human genetics, Vol.108(7), pp.1301-1317
Publisher: Elsevier Inc
Identifiers: 9920421008331
Academic Unit: King Abdulaziz University; King Abdullah University of Science & Technology
Language: English
Resource Type: Journal article