1. Loss of C2orf69 defines a fatal autoinflammatory syndrome in humans and zebrafish that evokes a glycogen-storage-associated mitochondriopathy
- Author
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Fatma Gumruk, Guoliang Chai, Bertrand Boisson, Natalia Ordonez, Ricardo Moreno Traspas, Maha S. Zaki, Stephanie Efthymiou, Dana Hasbini, Sze Hwee Seet, Thanh Thao Nguyen Ly, Jean-Laurent Casanova, Tadahiro Mitani, Michael Maier, Danielle Sng, Pelin Ozlem Simsek-Kiper, Davut Pehlivan, Hülya Kayserili, James R. Lupski, Nese Yarali, Kornelia Tripolszki, Abigail Loh, Hui Hui Wong, Robert J. Isfort, Joshua J. Coon, Sedat Işıkay, Frederic Bard, Ece Cepni, Evgenia Shishkova, Charles C. Bascom, Chao Liang, Afaf Alsubhi, Bruno Reversade, Nurten A. Akarsu, Tze Shin Teoh, Jarred W. Rensvold, Nima Rezaei, Soh Sok Keng, David J. Pagliarini, Serdar Ceylaner, Naser Gilani, Lena Ho, Fatima Megala Nathan, Siew Chin Choo, Hamdi Mbarek, Crystal Y. Chia, Wafaa Eyaid, Ozlem Arman-Bilir, Reza Maroofian, Simin Seyedpour, Kortessa Sotiropoulou, Joseph G. Gleeson, Peter Bauer, Arda Cetinkaya, Beril Talim, Fernanda L. Sirota, Sule Unal, Ghamar Taj Khotaei, Sebastian Maurer-Stroh, Franziska Paul, Shan Zhang, Elanur Yılmaz, Ayse Gurel, Shifeng Xue, Henry Houlden, Ajay S. Mathuru, Myriam Chaabouni, Aida M. Bertoli-Avella, Candice Lainé, Cheryl Yi-Pin Lee, Danai Georgiadou, Nur Ain Ali, Deniz Uğurlu Çi̇men, Graduate School, ACS - Diabetes & metabolism, APH - Mental Health, and ARD - Amsterdam Reproduction and Development
- Subjects
Male ,Proband ,Mitochondrial Diseases ,GBE1 ,C2ORF69, mitochondriopathy, inflammation, GBE1, encephalopathy, zebrafish, Elbracht-Işikay syndrome, lipase, glycogen, Mendelian genetics ,Mitochondrion ,Bioinformatics ,Leukoencephalopathy ,chemistry.chemical_compound ,0302 clinical medicine ,lipase ,Medicine ,Zebrafish ,Genetics (clinical) ,Genetics ,0303 health sciences ,Glycogen ,biology ,encephalopathy ,Biological Evolution ,Pedigree ,mitochondriopathy ,glycogen ,Encephalitis ,Female ,Elbracht-Işikay syndrome ,Encephalopathy ,Genes, Recessive ,C2ORF69 ,Article ,Cell Line ,03 medical and health sciences ,Seizures ,Glycogen branching enzyme ,Animals ,Humans ,Gene ,030304 developmental biology ,business.industry ,Correction ,Membrane Proteins ,Regret ,zebrafish ,medicine.disease ,Autoinflammatory Syndrome ,biology.organism_classification ,Human genetics ,chemistry ,inflammation ,Mendelian genetics ,biology.protein ,CRISPR-Cas Systems ,business ,030217 neurology & neurosurgery - 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.
- Published
- 2021
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