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

Journal of Clinical Investigation, vol. 131

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.

Authors 33

1. Eva Lausberg Aachen Institute of Human Genetics Medical Faculty

   RWTH Aachen University

   Affiliation as printed

   Institute of Human Genetics, Medical Faculty, Rheinisch-Westfaelische Technische Hochschule (RWTH) Aachen University, Aachen, Germany

2. Sebastian Gießelmann Aachen Institute of Human Genetics Medical Faculty

   RWTH Aachen University

   Affiliation as printed

   Institute of Human Genetics, Medical Faculty, Rheinisch-Westfaelische Technische Hochschule (RWTH) Aachen University, Aachen, Germany

3. Joseph P. Dewulf

   Cliniques Universitaires Saint-Luc · de Duve Institute · UCLouvain

   Affiliation as printed

   Department of Laboratory Medicine, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium

   Laboratory of Physiological Chemistry, de Duve Institute and

4. Elsa Wiame

   de Duve Institute

   Affiliation as printed

   Laboratory of Physiological Chemistry, de Duve Institute and

5. Anja Holz

   Praxis für Humangenetik Tübingen · CeGaT (Germany)

   Affiliation as printed

   CeGaT GmbH and Praxis für Humangenetik, Tübingen, Germany

6. Ramona Salvarinova

   University of British Columbia · BC Children's Hospital · BC Children's Hospital Research Institute

   Affiliation as printed

   British Columbia Children's Hospital Research Institute, University of British Columbia (UBC), Vancouver, British Columbia, Canada

   Division of Biochemical Diseases, Department of Pediatrics, British Columbia Children's Hospital Vancouver, Vancouver, British Columbia, Canada

7. Clara D.M. van Karnebeek

   University of British Columbia · Radboud University Nijmegen · Radboud University Medical Center

   Affiliation as printed

   Department of Pediatrics, Centre for Molecular Medicine and Therapeutics, UBC, Vancouver, British Columbia, Canada

   Department of Pediatrics, Radboud Centre for Mitochondrial Medicine, Radboud University Medical Centre, Nijmegen, Netherlands

8. Patricia Klemm
   Affiliation as printed

   Department of Pediatrics, Medical Faculty

   Department of Pediatrics, Medical Faculty,

9. Kim Ohl
   Affiliation as printed

   Department of Pediatrics, Medical Faculty

   Department of Pediatrics, Medical Faculty,

10. Michael Mull
    Affiliation as printed

    Department of Diagnostic and Interventional Neuroradiology, Medical Faculty

    Department of Diagnostic and Interventional Neuroradiology, Medical Faculty,

11. Till A. Braunschweig
    Affiliation as printed

    Institute of Pathology, Medical Faculty, and

12. Joachim Weis Aachen Institute of Neuropathology, Medical Faculty

    RWTH Aachen University

    Affiliation as printed

    Institute of Neuropathology, Medical Faculty, RWTH University, Aachen, Germany

13. Clemens J. Sommer

    Johannes Gutenberg University Mainz · University Medical Center of the Johannes Gutenberg University Mainz

    Affiliation as printed

    Institute of Neuropathology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany

14. Stephanie Demuth
    Affiliation as printed

    Praxis für Humangenetik Erfurt, Erfurt, Germany

15. Claudia Stollbrink-Peschgens
    Affiliation as printed

    Department of Pediatrics, Medical Faculty

    Department of Pediatrics, Medical Faculty,

16. François‐Guillaume Debray

    Centre Hospitalier Universitaire de Liège

    Affiliation as printed

    Department of Human Genetics, Centre Hospitalier Universitaire (CHU) de Liège, Liège, Belgium

17. Cécile Libioulle

    Centre Hospitalier Universitaire de Liège

    Affiliation as printed

    Department of Human Genetics, Centre Hospitalier Universitaire (CHU) de Liège, Liège, Belgium

18. Daniela Choukair

    Heidelberg University

    Affiliation as printed

    Department of General Pediatrics, University Children's Hospital, Heidelberg University, Heidelberg, Germany

19. Prasad T. Oommen
    Affiliation as printed

    Department of Pediatric Oncology, Hematology, and Clinical Immunology, University Children's Hospital, Medical Faculty and

20. Arndt Borkhardt
    Affiliation as printed

    Department of Pediatric Oncology, Hematology, and Clinical Immunology, University Children's Hospital, Medical Faculty and

21. Harald Surowy

    Heinrich Heine University Düsseldorf

    Affiliation as printed

    Institute of Human Genetics, Medical Faculty, Heinrich-Heine University (HHU), Düsseldorf, Germany

22. Dagmar Wieczorek

    Heinrich Heine University Düsseldorf

    Affiliation as printed

    Institute of Human Genetics, Medical Faculty, Heinrich-Heine University (HHU), Düsseldorf, Germany

23. Norbert Wagner
    Affiliation as printed

    Department of Pediatrics, Medical Faculty

    Department of Pediatrics, Medical Faculty,

24. Robert Meyer Aachen Institute of Human Genetics Medical Faculty

    RWTH Aachen University

    Affiliation as printed

    Institute of Human Genetics, Medical Faculty, Rheinisch-Westfaelische Technische Hochschule (RWTH) Aachen University, Aachen, Germany

25. Thomas Eggermann Aachen Institute of Human Genetics Medical Faculty

    RWTH Aachen University

    Affiliation as printed

    Institute of Human Genetics, Medical Faculty, Rheinisch-Westfaelische Technische Hochschule (RWTH) Aachen University, Aachen, Germany

26. Matthias Begemann Aachen Institute of Human Genetics Medical Faculty

    RWTH Aachen University

    Affiliation as printed

    Institute of Human Genetics, Medical Faculty, Rheinisch-Westfaelische Technische Hochschule (RWTH) Aachen University, Aachen, Germany

27. Emile VAN SCHAFTINGEN

    de Duve Institute

    Affiliation as printed

    Laboratory of Physiological Chemistry, de Duve Institute and

28. Martin Häusler
    Affiliation as printed

    Department of Pediatrics, Medical Faculty

    Department of Pediatrics, Medical Faculty,

29. Klaus Tenbrock
    Affiliation as printed

    Department of Pediatrics, Medical Faculty

    Department of Pediatrics, Medical Faculty,

30. Lambert van den Heuvel

    Radboud University Nijmegen · Radboud University Medical Center

    Affiliation as printed

    Department of Pediatrics, Translational Metabolic Laboratory at the Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, Netherlands

31. Miriam Elbracht Aachen Institute of Human Genetics Medical Faculty

    RWTH Aachen University

    Affiliation as printed

    Institute of Human Genetics, Medical Faculty, Rheinisch-Westfaelische Technische Hochschule (RWTH) Aachen University, Aachen, Germany

32. Ingo Kurth Aachen Institute of Human Genetics Medical Faculty

    RWTH Aachen University

    Affiliation as printed

    Institute of Human Genetics, Medical Faculty, Rheinisch-Westfaelische Technische Hochschule (RWTH) Aachen University, Aachen, Germany

33. Florian Kraft corresponding Aachen Institute of Human Genetics Medical Faculty

    RWTH Aachen University

    Affiliation as printed

    Institute of Human Genetics, Medical Faculty, Rheinisch-Westfaelische Technische Hochschule (RWTH) Aachen University, Aachen, Germany