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

TitleLoss of C2orf69 defines a fatal autoinflammatory syndrome in humans and zebrafish that evokes a glycogen-storage-associated mitochondriopathy.
Publication TypeJournal Article
Year of Publication2021
AuthorsWong, HHui, Seet, SHwee, Maier, M, Gurel, A, Traspas, RMoreno, Lee, C, Zhang, S, Talim, B, Loh, AYT, Chia, CY, Teoh, TShin, Sng, D, Rensvold, J, Unal, S, Shishkova, E, Cepni, E, Nathan, FM, Sirota, FL, Liang, C, Yarali, N, Simsek-Kiper, PO, Mitani, T, Ceylaner, S, Arman-Bilir, O, Mbarek, H, Gumruk, F, Efthymiou, S, Men, DUğurlu Ç, Georgiadou, D, Sotiropoulou, K, Houlden, H, Paul, F, Pehlivan, D, Lainé, C, Chai, G, Ali, NAin, Choo, SChin, Keng, SSok, Boisson, B, Yılmaz, E, Xue, S, Coon, JJ, Ly, TThao Nguye, Gilani, N, Hasbini, D, Kayserili, H, Zaki, MS, Isfort, RJ, Ordonez, N, Tripolszki, K, Bauer, P, Rezaei, N, Seyedpour, S, Khotaei, GTaj, Bascom, CC, Maroofian, R, Chaabouni, M, Alsubhi, A, Eyaid, W, Isikay, S, Gleeson, JG, Lupski, JR, Casanova, J-L, Pagliarini, DJ, Akarsu, NA, Maurer-Stroh, S, Cetinkaya, A, Bertoli-Avella, A, Mathuru, AS, Ho, L, Bard, FA, Reversade, B
JournalAm J Hum Genet
Date Published2021 07 01
KeywordsAnimals, Biological Evolution, Cell Line, CRISPR-Cas Systems, Encephalitis, Female, Genes, Recessive, Glycogen, Humans, Inflammation, Male, Membrane Proteins, Mitochondrial Diseases, Pedigree, Seizures, Zebrafish

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.

Alternate JournalAm J Hum Genet
PubMed ID34038740
PubMed Central IDPMC8322802
Grant ListR35 GM131795 / GM / NIGMS NIH HHS / United States
R35 NS105078 / NS / NINDS NIH HHS / United States