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

Authors

Lausberg E¹, Gießelmann S¹, Dewulf JP², Wiame E², Holz A³, Salvarinova R⁴, van Karnebeek CD⁵, Klemm P⁶, Ohl K⁶, Mull M⁷, Braunschweig T⁸, Weis J⁹, Sommer CJ¹⁰, Demuth S¹¹, Haase C¹², Stollbrink-Peschgens C⁶, Debray FG¹³, Libioulle C¹³, Choukair D¹⁴, Oommen PT¹⁵, Borkhardt A¹⁵, Surowy H¹⁶, Wieczorek D¹⁶, Wagner N⁶, Meyer R¹, Eggermann T¹, Begemann M¹, van Schaftingen E², Häusler M⁶, Tenbrock K⁶, van den Heuvel L¹⁷, Elbracht M¹, Kurth I¹, Kraft F¹

Institute of Human Genetics, RWTH Aachen University, Aachen, Germany.
Laboratory of Physiological Chemistry, de Duve Institute, Université Catholique de Louvain, Brussels, Belgium.
Praxis für Humangenetik, CeGaT GmbH, Tübingen, Germany.
Department of Pediatrics, British Columbia Children’s Hospital Vancouver, Vancouver, Canada.
Centre for Mitochondrial Medicine, Radboud University Medical Centre, Nijmegen, Netherlands.
Department of Pediatrics, RWTH Aachen University, Aachen, Germany.
Department of Diagnostic and Interventional Neuroradiology, RWTH Aachen University, Aachen, Germany.
Institute of Pathology, RWTH Aachen University, Aachen, Germany.
Institute of Neuropathology, RWTH Aachen University Hospital, Aachen, Germany.
Institute of Neuropathology, University Mainz, Mainz, Germany.
Humangenetik, Praxis für Humangenetik Erfurt, Erfurt, Germany.
Ambulanz für angeborene Stoffwechselerkrankungen, Helios Klinikum Erfurt, Erfurt, Germany.
Department of Human Genetics, CHU de Liège, Liège, Belgium.
Department of General Pediatrics, University Heidelberg, Heidelberg, Germany.
Department of Pediatric Oncology, Heinrich-Heine University Dusseldorf, Düsseldorf, Germany.
Institute of Human Genetics, Heinrich-Heine University Dusseldorf, Düsseldorf, Germany.
Department of Pediatrics, Radboud University Medical Centre, Nijmegen, Netherlands.

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 identified 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 showed signs of respiratory chain defect and a CRISPR-Cas9 knockout cell model of C2orf69 had similar respiratory chain defects. Patient-derived cells revealed alterations in immunological signaling pathways. Deposits of 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 an additional influence on other metabolic pathways.

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