C2orf69 mutations disrupt mitochondrial function and cause a multisystem human disorder with recurring autoinflammation
| Autor: | Claudia Stollbrink-Peschgens, Patricia Klemm, Lambert P. van den Heuvel, Ingo Kurth, Clara D.M. van Karnebeek, Michael Mull, Eva Lausberg, C. Libioulle, Robert Meyer, Thomas Eggermann, Emile Van Schaftingen, Klaus Tenbrock, Daniela Choukair, Joseph P. Dewulf, François-Guillaume Debray, Joachim Weis, Kim Ohl, Norbert Wagner, Prasad T Oommen, Claudia Haase, Elsa Wiame, Dagmar Wieczorek, Arndt Borkhardt, Matthias Begemann, Sebastian Gießelmann, Anja Holz, Florian Kraft, Harald Surowy, Miriam Elbracht, Clemens Sommer, Ramona Salvarinova, Stephanie Demuth, Till Braunschweig, Martin Häusler |
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| Přispěvatelé: | ANS - Cellular & Molecular Mechanisms, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, UCL - SSS/DDUV/BCHM - Biochimie-Recherche métabolique, UCL - (SLuc) Service de biochimie médicale |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Microcephaly Respiratory chain Biology Mitochondrion Cell Line Mitochondrial Proteins Transcriptome Mice Open Reading Frames 03 medical and health sciences All institutes and research themes of the Radboud University Medical Center 0302 clinical medicine Loss of Function Mutation Glycogen branching enzyme medicine Animals Humans Gene Mice Knockout Genetics Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6] Glycogen Debranching Enzyme System General Medicine medicine.disease Mitochondria Open reading frame Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11] 030104 developmental biology 030220 oncology & carcinogenesis biology.protein Clinical Medicine Signal transduction Glycogen |
| Zdroj: | Journal of Clinical Investigation, 131 J Clin Invest Journal of clinical investigation, 131(12):e143078. The American Society for Clinical Investigation The Journal of clinical investigation, Vol. 131, no. 12, p. e143078 [1-13] (2021) Journal of Clinical Investigation, 131, 12 Journal of Clinical Investigation, Vol. 131, no.12 (2021) |
| ISSN: | 1558-8238 0021-9738 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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