Lausberg E1, Gießelmann S1, Dewulf JP2, Wiame E2, Holz A3, Salvarinova R4, van Karnebeek CD5, Klemm P6, Ohl K6, Mull M7, Braunschweig T8, Weis J9, Sommer CJ10, Demuth S11, Haase C12, Stollbrink-Peschgens C6, Debray FG13, Libioulle C13, Choukair D14, Oommen PT15, Borkhardt A15, Surowy H16, Wieczorek D16, Wagner N6, Meyer R1, Eggermann T1, Begemann M1, van Schaftingen E2, Häusler M6, Tenbrock K6, van den Heuvel L17, Elbracht M1, Kurth I1, Kraft F1
Background: Deciphering the function of the many genes previously classified as uncharacterized “open reading frame” (orf) completes our understanding of cell function and its pathophysiology.
Methods: Whole-exome sequencing, yeast 2-hybrid and transcriptome analyses together with molecular characterization are used here to uncover the function of the C2orf69 gene.
Results: We identified loss-of-function mutations in the uncharacterized C2orf69 gene in eight 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, patients showed signs of respiratory chain defect and a CRISPR-Cas9 knockout cell model of C2orf69 had similar respiratory chain defects. Patient-derived cells revealed alterations in immunological signaling pathways. Deposits of 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.
Conclusions: Our study identifies C2orf69 as an important regulator of human mitochondrial function and suggests an additional influence on other metabolic pathways.
- Institute of Human Genetics, RWTH Aachen University, Aachen, Germany..
- Laboratory of Physiological Chemistry, de Duve Institute, Université Catholique de Louvain, Brussels, Belgium.
- Praxis für Humangenetik, CeGaT GmbH, Tübingen, Germany.
- Department of Pediatrics, British Columbia Children’s Hospital Vancouver, Vancouver, Canada.
- Centre for Mitochondrial Medicine, Radboud University Medical Centre, Nijmegen, Netherlands.
- Department of Pediatrics, RWTH Aachen University, Aachen, Germany.
- Department of Diagnostic and Interventional Neuroradiology, RWTH Aachen University, Aachen, Germany.
- Institute of Pathology, RWTH Aachen University, Aachen, Germany.
- Institute of Neuropathology, RWTH Aachen University Hospital, Aachen, Germany.
- Institute of Neuropathology, University Mainz, Mainz, Germany.
- Humangenetik, Praxis für Humangenetik Erfurt, Erfurt, Germany.
- Ambulanz für angeborene Stoffwechselerkrankungen, Helios Klinikum Erfurt, Erfurt, Germany.
- Department of Human Genetics, CHU de Liège, Liège, Belgium.
- Department of General Pediatrics, University Heidelberg, Heidelberg, Germany.
- Department of Pediatric Oncology, Heinrich-Heine University Dusseldorf, Düsseldorf, Germany.
- Institute of Human Genetics, Heinrich-Heine University Dusseldorf, Düsseldorf, Germany.
- Department of Pediatrics, Radboud University Medical Centre, Nijmegen, Netherlands.