6533b7dcfe1ef96bd12729bb
RESEARCH PRODUCT
C2orf69 mutations disrupt mitochondrial function and cause a multisystem human disorder with recurring autoinflammation
Claudia Stollbrink-peschgensPatricia KlemmLambert P. Van Den HeuvelIngo KurthClara D.m. Van KarnebeekMichael MullEva LausbergC. LibioulleRobert MeyerThomas EggermannEmile Van SchaftingenKlaus TenbrockDaniela ChoukairJoseph P. DewulfFrançois-guillaume DebrayJoachim WeisKim OhlNorbert WagnerPrasad T OommenClaudia HaaseElsa WiameDagmar WieczorekArndt BorkhardtMatthias BegemannSebastian GießelmannAnja HolzFlorian KraftHarald SurowyMiriam ElbrachtClemens SommerRamona SalvarinovaStephanie DemuthTill BraunschweigMartin Häuslersubject
0301 basic medicineMicrocephalyRespiratory chainBiologyMitochondrionCell LineMitochondrial ProteinsTranscriptomeMiceOpen Reading Frames03 medical and health sciencesAll institutes and research themes of the Radboud University Medical Center0302 clinical medicineLoss of Function MutationGlycogen branching enzymemedicineAnimalsHumansGeneMice KnockoutGeneticsMetabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6]Glycogen Debranching Enzyme SystemGeneral Medicinemedicine.diseaseMitochondriaOpen reading frameRenal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11]030104 developmental biology030220 oncology & carcinogenesisMicrocephalybiology.proteinClinical MedicineSignal transductionGlycogendescription
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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2021-06-01 | Journal of Clinical Investigation |