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


Wong H. H. , Seet S. H. , Maier M., GÜREL A., Traspas R. M. , Lee C., ...More

AMERICAN JOURNAL OF HUMAN GENETICS, vol.108, no.7, pp.1301-1317, 2021 (Peer-Reviewed Journal) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 108 Issue: 7
  • Publication Date: 2021
  • Doi Number: 10.1016/j.ajhg.2021.05.003
  • Journal Name: AMERICAN JOURNAL OF HUMAN GENETICS
  • Journal Indexes: Science Citation Index Expanded, Scopus, Academic Search Premier, International Bibliography of Social Sciences, BIOSIS, CAB Abstracts, Chemical Abstracts Core, CINAHL, EMBASE, MEDLINE, Veterinary Science Database
  • Page Numbers: pp.1301-1317

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.