BACKGROUND Deciphering 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.METHODS Whole-exome sequencing, yeast 2-hybrid and transcriptome analyses, and molecular characterization were performed in this study to uncover the function of the C2orf69 gene.RESULTS We 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.CONCLUSIONS Our study identifies C2orf69 as an important regulator of human mitochondrial function and suggests that this gene has additional influence on other metabolic pathways.
Eva Lausberg, Sebastian Gießelmann, Joseph P. Dewulf, Elsa Wiame, Anja Holz, Ramona Salvarinova, Clara D. van Karnebeek, Patricia Klemm, Kim Ohl, Michael Mull, Till Braunschweig, Joachim Weis, Clemens J. Sommer, Stephanie Demuth, Claudia Haase, Claudia Stollbrink-Peschgens, François-Guillaume Debray, Cecile Libioulle, Daniela Choukair, Prasad T. Oommen, Arndt Borkhardt, Harald Surowy, Dagmar Wieczorek, Norbert Wagner, Robert Meyer, Thomas Eggermann, Matthias Begemann, Emile Van Schaftingen, Martin Häusler, Klaus Tenbrock, Lambert van den Heuvel, Miriam Elbracht, Ingo Kurth, Florian Kraft