TY - JOUR
T1 - C2orf69 mutations disrupt mitochondrial function and cause a multisystem human disorder with recurring autoinflammation
AU - Lausberg, Eva
AU - Gießelmann, Sebastian
AU - Dewulf, Joseph P.
AU - Wiame, Elsa
AU - Holz, Anja
AU - Salvarinova, Ramona
AU - van Karnebeek, Clara D.
AU - Klemm, Patricia
AU - Ohl, Kim
AU - Mull, Michael
AU - Braunschweig, Till
AU - Weis, Joachim
AU - Sommer, Clemens J.
AU - Demuth, Stephanie
AU - Haase, Claudia
AU - Stollbrink-Peschgens, Claudia
AU - Debray, François-Guillaume
AU - Libioulle, Cecile
AU - Choukair, Daniela
AU - Oommen, Prasad T.
AU - Borkhardt, Arndt
AU - Surowy, Harald
AU - Wieczorek, Dagmar
AU - Wagner, Norbert
AU - Meyer, Robert
AU - Eggermann, Thomas
AU - Begemann, Matthias
AU - van Schaftingen, Emile
AU - Häusler, Martin
AU - Tenbrock, Klaus
AU - van den Heuvel, Lambert
AU - Elbracht, Miriam
AU - Kurth, Ingo
AU - Kraft, Florian
N1 - Funding Information: This work was funded by the Deutsche Forschungsgemeinschaft (DFG) (948/32–1 FUGG). Support for this study was provided by the Flow Cytometry Facility and the Genomics Facility, core facilities of the Interdisciplinary Center for Clinical Research (IZKF) Aachen within the Faculty of Medicine at RWTH Aachen University. The study was also supported by a Fund Invest for Scientific Research (FIRS) grant from the CHU de Liège, Belgium. We are grateful to the TIDEX team (Britt Drogemoller, Aisha Ghani, Colin Ross, Maja Tarailo-Graovac, and Wyeth Wassermann) at the UBC’s Centre for Molecular Medicine and Therapeutics (Vancouver, British Columbia, Canada). We also acknowledge the phy- sicians who participated in the patients’ clinical care: Hal Siden, Canuck Place, Michelle Demos, and Lori Tucker (Department of Pediatrics, British Columbia Children’s Hospital). Publisher Copyright: Copyright: © 2021, American Society for Clinical Investigation.
PY - 2021/6/1
Y1 - 2021/6/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85108286674&partnerID=8YFLogxK
U2 - https://doi.org/10.1172/JCI143078
DO - https://doi.org/10.1172/JCI143078
M3 - Article
C2 - 33945503
SN - 0021-9738
VL - 131
JO - Journal of clinical investigation
JF - Journal of clinical investigation
IS - 12
M1 - e143078
ER -