A human multisystem disorder with autoinflammation, leukoencephalopathy and hepatopathy is caused by mutations in C2orf69
2021
Background: Unraveling the function of the many genes that encode for uncharacterized open reading frames (ORFs) is important to understand physiological processes. Methods: By whole exome sequencing, yeast-2-hybrid, transcriptome analysis and molecular characterization we could uncover the cause of an undescribed mitochondriopathy. Results: We identify loss-of-function mutations in the uncharacterized C2orf69 gene in eight individuals with a common phenotype of brain anomalies with hypomyelination and microcephaly, liver dysfunction, and recurrent autoinflammation of tissue and bones. C2orf69 is targeted to mitochondria by an N-terminal signal peptide which is both required and sufficient for mitochondrial localization. In line with a mitochondrial disorder the patients show signs of a respiratory chain defect and a CRISPR-Cas9 knockout cell model of C2orf69 resembles these respiratory chain defects. Patient-derived cells reveal an alteration of immunological pathways. Deposits of PAS-positive material in tissues from affected individuals together with a decreased glycogen branching enzyme 1 (GBE1) activity indicate the additional impact of C2orf69 on glycogen metabolism. Conclusion: Our study identifies C2orf69 as important regulator of mitochondrial function and suggests an additional impact on other metabolic pathways.
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