A human multisystem disorder with autoinflammation, leukoencephalopathy and hepatopathy is caused by mutations in C2orf69
Abstract
Abstract 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 identify 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 show signs of respiratory chain defect and a CRISPR-Cas9 knockout cell model of C2orf69 shows comparable respiratory chain defects. Patient-derived cells reveal alterations in immunological signaling pathways. Deposits of PAS-positive material in tissues from affected individuals together with decreased glycogen branching enzyme 1 (GBE1) activity indicate an additional impact of C2orf69 on glycogen metabolism. Conclusion Our study identifies C2orf69 as an important regulator of human mitochondrial function and suggests an additional influence on other metabolic pathways. Graphical Abstract
Authors 31
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Affiliation as printed
Institute of Human Genetics, Medical Faculty, RWTH Aachen University, Aachen, Germany
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Affiliation as printed
Institute of Human Genetics, Medical Faculty, RWTH Aachen University, Aachen, Germany
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Cliniques Universitaires Saint-Luc · de Duve Institute · UCLouvain
Affiliation as printed
Department of Laboratory Medicine, Cliniques universitaires Saint-Luc, UC Louvain, Brussels, Belgium
Laboratory of Physiological Chemistry, de Duve Institute, UC Louvain, Brussels, Belgium
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Affiliation as printed
Laboratory of Physiological Chemistry, de Duve Institute, UC Louvain, Brussels, Belgium
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Praxis für Humangenetik Tübingen · CeGaT (Germany)
Affiliation as printed
CeGaT GmbH, and Praxis für Humangenetik, Tübingen, Germany
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University of British Columbia · BC Children's Hospital · BC Children's Hospital Research Institute
Affiliation as printed
BC Children’s Hospital Research Institute, UBC, Vancouver, Canada
Division of Biochemical Diseases, Department of Pediatrics, British Columbia Children’s Hospital Vancouver, Vancouver, Canada
BC Children's Hospital Research Institute, UBC, Vancouver, Canada
Division of Biochemical Diseases, Department of Pediatrics, British Columbia Children's Hospital Vancouver, Vancouver, Canada
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University of British Columbia · Radboud University Nijmegen · Radboud University Medical Center
Affiliation as printed
Department of Pediatrics, Centre for Molecular Medicine and Therapeutics, UBC, Vancouver, Canada
Department of Pediatrics, Radboud Centre for Mitochondrial Medicine, Radboudumc, Nijmegen, Netherlands
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Affiliation as printed
Department of Pediatrics, RWTH Aachen University, Aachen, Germany
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Affiliation as printed
Department of Pediatrics, RWTH Aachen University, Aachen, Germany
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Affiliation as printed
Department of Diagnostic and Interventional Neuroradiology, Medical Faculty, RWTH Aachen University, Aachen, Germany
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Affiliation as printed
Institute of Pathology, Medical Faculty, RWTH Aachen University, Aachen, Germany
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Universitätsklinikum Aachen · RWTH Aachen University
Affiliation as printed
Institute of Neuropathology, Medical Faculty, RWTH University Hospital, Aachen, Germany
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Johannes Gutenberg University Mainz · University Medical Center of the Johannes Gutenberg University Mainz
Affiliation as printed
Institute of Neuropathology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
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Affiliation as printed
Praxis für Humangenetik Erfurt, Erfurt, Germany
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Centre Hospitalier Universitaire de Liège
Affiliation as printed
Department of Human Genetics - CHU de Liège, Liege, Belgium
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Centre Hospitalier Universitaire de Liège
Affiliation as printed
Department of Human Genetics - CHU de Liège, Liege, Belgium
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Affiliation as printed
Department of General Pediatrics, University Children’s Hospital, University Heidelberg, Heidelberg, Germany
Department of General Pediatrics, University Children's Hospital, University Heidelberg, Heidelberg, Germany
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Heinrich Heine University Düsseldorf
Affiliation as printed
Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children’s Hospital, Medical Faculty, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany
Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children's Hospital, Medical Faculty, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany
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Heinrich Heine University Düsseldorf
Affiliation as printed
Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children’s Hospital, Medical Faculty, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany
Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children's Hospital, Medical Faculty, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany
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Heinrich Heine University Düsseldorf
Affiliation as printed
Institute of Human Genetics, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
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Heinrich Heine University Düsseldorf
Affiliation as printed
Institute of Human Genetics, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
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Affiliation as printed
Institute of Human Genetics, Medical Faculty, RWTH Aachen University, Aachen, Germany
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Affiliation as printed
Institute of Human Genetics, Medical Faculty, RWTH Aachen University, Aachen, Germany
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Affiliation as printed
Institute of Human Genetics, Medical Faculty, RWTH Aachen University, Aachen, Germany
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Affiliation as printed
Laboratory of Physiological Chemistry, de Duve Institute, UC Louvain, Brussels, Belgium
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Affiliation as printed
Department of Pediatrics, RWTH Aachen University, Aachen, Germany
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Affiliation as printed
Department of Pediatrics, RWTH Aachen University, Aachen, Germany
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Radboud University Nijmegen · Radboud University Medical Center
Affiliation as printed
Department of Pediatrics, Translational Metabolic Laboratory at Department of Laboratory Medicine, Radboudumc, Nijmegen, Netherlands
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Affiliation as printed
Institute of Human Genetics, Medical Faculty, RWTH Aachen University, Aachen, Germany
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Affiliation as printed
Institute of Human Genetics, Medical Faculty, RWTH Aachen University, Aachen, Germany
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Affiliation as printed
Institute of Human Genetics, Medical Faculty, RWTH Aachen University, Aachen, Germany
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