C2orf69 mutations disrupt mitochondrial function and cause a multisystem human disorder with recurring autoinflammation

  • J Clin Invest. 2021 Jun 15;131(12):e143078. doi: 10.1172/JCI143078.
Eva Lausberg  1 ,  Sebastian Gießelmann  1 ,  Joseph P Dewulf  2  3 ,  Elsa Wiame  2 ,  Anja Holz  4 ,  Ramona Salvarinova  5  6 ,  Clara D van Karnebeek  7  8 ,  Patricia Klemm  9 ,  Kim Ohl  9 ,  Michael Mull  10 ,  Till Braunschweig  11 ,  Joachim Weis  12 ,  Clemens J Sommer  13 ,  Stephanie Demuth  14 ,  Claudia Haase  15 ,  Claudia Stollbrink-Peschgens  9 ,  François-Guillaume Debray  16 ,  Cecile Libioulle  16 ,  Daniela Choukair  17 ,  Prasad T Oommen  18 ,  Arndt Borkhardt  18 ,  Harald Surowy  19 ,  Dagmar Wieczorek  19 ,  Norbert Wagner  9 ,  Robert Meyer  1 ,  Thomas Eggermann  1 ,  Matthias Begemann  1 ,  Emile Van Schaftingen  2 ,  Martin Häusler  9 ,  Klaus Tenbrock  9 ,  Lambert van den Heuvel  20 ,  Miriam Elbracht  1 ,  Ingo Kurth  1 ,  Florian Kraft  1
Affiliations
  • 1. Institute of Human Genetics, Medical Faculty, Rheinisch-Westfaelische Technische Hochschule (RWTH) Aachen University, Aachen, Germany.
  • 2. Laboratory of Physiological Chemistry, de Duve Institute and.
  • 3. Department of Laboratory Medicine, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.
  • 4. CeGaT GmbH and Praxis für Humangenetik, Tübingen, Germany.
  • 5. Division of Biochemical Diseases, Department of Pediatrics, British Columbia Children's Hospital Vancouver, Vancouver, British Columbia, Canada.
  • 6. British Columbia Children's Hospital Research Institute, University of British Columbia (UBC), Vancouver, British Columbia, Canada.
  • 7. Department of Pediatrics, Radboud Centre for Mitochondrial Medicine, Radboud University Medical Centre, Nijmegen, Netherlands.
  • 8. Department of Pediatrics, Centre for Molecular Medicine and Therapeutics, UBC, Vancouver, British Columbia, Canada.
  • 9. Department of Pediatrics, Medical Faculty.
  • 10. Department of Diagnostic and Interventional Neuroradiology, Medical Faculty.
  • 11. Institute of Pathology, Medical Faculty, and.
  • 12. Institute of Neuropathology, Medical Faculty, RWTH University, Aachen, Germany.
  • 13. Institute of Neuropathology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
  • 14. Praxis für Humangenetik Erfurt, Erfurt, Germany.
  • 15. HELIOS Klinikum Erfurt, Ambulanz für Angeborene Stoffwechselerkrankungen, Sozialpädiatrisches Zentrum, Erfurt, Germany.
  • 16. Department of Human Genetics, Centre Hospitalier Universitaire (CHU) de Liège, Liège, Belgium.
  • 17. Department of General Pediatrics, University Children's Hospital, Heidelberg University, Heidelberg, Germany.
  • 18. Department of Pediatric Oncology, Hematology, and Clinical Immunology, University Children's Hospital, Medical Faculty and.
  • 19. Institute of Human Genetics, Medical Faculty, Heinrich-Heine University (HHU), Düsseldorf, Germany.
  • 20. Department of Pediatrics, Translational Metabolic Laboratory at the Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, Netherlands.
PMID: 33945503 DOI: 10.1172/JCI143078
Abstract

BACKGROUNDDeciphering the function of the many genes previously classified as uncharacterized open reading frame (ORF) would complete our understanding of a cell's function and its pathophysiology.METHODSWhole-exome Sequencing, yeast 2-hybrid and transcriptome analyses, and molecular characterization were performed in this study to uncover the function of the C2orf69 gene.RESULTSWe identified loss-of-function mutations in the uncharacterized C2orf69 gene in 8 individuals with brain abnormalities involving hypomyelination and microcephaly, liver dysfunction, and recurrent autoinflammation. C2orf69 contains an N-terminal signal peptide that is required and sufficient for mitochondrial localization. Consistent with mitochondrial dysfunction, the patients showed signs of respiratory chain defects, and a CRISPR/Cas9-KO cell model of C2orf69 had similar respiratory chain defects. Patient-derived cells revealed alterations in immunological signaling pathways. Deposits of periodic acid-Schiff-positive (PAS-positive) material in tissues from affected individuals, together with decreased glycogen branching enzyme 1 (GBE1) activity, indicated an additional impact of C2orf69 on glycogen metabolism.CONCLUSIONSOur study identifies C2orf69 as an important regulator of human mitochondrial function and suggests that this gene has additional influence on Other metabolic pathways.

Keywords
Genetic diseases; Genetics; Mitochondria; Neurological disorders.