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

Autor: Lausberg E; Institute of Human Genetics, Medical Faculty, Rheinisch-Westfaelische Technische Hochschule (RWTH) Aachen University, Aachen, Germany., Gießelmann S; Institute of Human Genetics, Medical Faculty, Rheinisch-Westfaelische Technische Hochschule (RWTH) Aachen University, Aachen, Germany., Dewulf JP; Laboratory of Physiological Chemistry, de Duve Institute and.; Department of Laboratory Medicine, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium., Wiame E; Laboratory of Physiological Chemistry, de Duve Institute and., Holz A; CeGaT GmbH and Praxis für Humangenetik, Tübingen, Germany., Salvarinova R; Division of Biochemical Diseases, Department of Pediatrics, British Columbia Children's Hospital Vancouver, Vancouver, British Columbia, Canada.; British Columbia Children's Hospital Research Institute, University of British Columbia (UBC), Vancouver, British Columbia, Canada., van Karnebeek CD; Department of Pediatrics, Radboud Centre for Mitochondrial Medicine, Radboud University Medical Centre, Nijmegen, Netherlands.; Department of Pediatrics, Centre for Molecular Medicine and Therapeutics, UBC, Vancouver, British Columbia, Canada., Klemm P; Department of Pediatrics, Medical Faculty., Ohl K; Department of Pediatrics, Medical Faculty., Mull M; Department of Diagnostic and Interventional Neuroradiology, Medical Faculty., Braunschweig T; Institute of Pathology, Medical Faculty, and., Weis J; Institute of Neuropathology, Medical Faculty, RWTH University, Aachen, Germany., Sommer CJ; Institute of Neuropathology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany., Demuth S; Praxis für Humangenetik Erfurt, Erfurt, Germany., Haase C; HELIOS Klinikum Erfurt, Ambulanz für Angeborene Stoffwechselerkrankungen, Sozialpädiatrisches Zentrum, Erfurt, Germany., Stollbrink-Peschgens C; Department of Pediatrics, Medical Faculty., Debray FG; Department of Human Genetics, Centre Hospitalier Universitaire (CHU) de Liège, Liège, Belgium., Libioulle C; Department of Human Genetics, Centre Hospitalier Universitaire (CHU) de Liège, Liège, Belgium., Choukair D; Department of General Pediatrics, University Children's Hospital, Heidelberg University, Heidelberg, Germany., Oommen PT; Department of Pediatric Oncology, Hematology, and Clinical Immunology, University Children's Hospital, Medical Faculty and., Borkhardt A; Department of Pediatric Oncology, Hematology, and Clinical Immunology, University Children's Hospital, Medical Faculty and., Surowy H; Institute of Human Genetics, Medical Faculty, Heinrich-Heine University (HHU), Düsseldorf, Germany., Wieczorek D; Institute of Human Genetics, Medical Faculty, Heinrich-Heine University (HHU), Düsseldorf, Germany., Wagner N; Department of Pediatrics, Medical Faculty., Meyer R; Institute of Human Genetics, Medical Faculty, Rheinisch-Westfaelische Technische Hochschule (RWTH) Aachen University, Aachen, Germany., Eggermann T; Institute of Human Genetics, Medical Faculty, Rheinisch-Westfaelische Technische Hochschule (RWTH) Aachen University, Aachen, Germany., Begemann M; Institute of Human Genetics, Medical Faculty, Rheinisch-Westfaelische Technische Hochschule (RWTH) Aachen University, Aachen, Germany., Van Schaftingen E; Laboratory of Physiological Chemistry, de Duve Institute and., Häusler M; Department of Pediatrics, Medical Faculty., Tenbrock K; Department of Pediatrics, Medical Faculty., van den Heuvel L; Department of Pediatrics, Translational Metabolic Laboratory at the Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, Netherlands., Elbracht M; Institute of Human Genetics, Medical Faculty, Rheinisch-Westfaelische Technische Hochschule (RWTH) Aachen University, Aachen, Germany., Kurth I; Institute of Human Genetics, Medical Faculty, Rheinisch-Westfaelische Technische Hochschule (RWTH) Aachen University, Aachen, Germany., Kraft F; Institute of Human Genetics, Medical Faculty, Rheinisch-Westfaelische Technische Hochschule (RWTH) Aachen University, Aachen, Germany.
Jazyk: angličtina
Zdroj: The Journal of clinical investigation [J Clin Invest] 2021 Jun 15; Vol. 131 (12).
DOI: 10.1172/JCI143078
Abstrakt: 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.
Databáze: MEDLINE