A novel variant in COX16 causes cytochrome c oxidase deficiency, severe fatal neonatal lactic acidosis, encephalopathy, cardiomyopathy, and liver dysfunction
Liesbeth TM Wintjes, Maina Kava, Frans A van den Brandt, Mariel AM van den Brand, Oksana Lapina, Yngve T Bliksrud, Mari A Kulseth, Silja S Amundsen, Terje R Selberg, Marion Ybema-Antoine, Omar AZ Tutakhel, Lawrence Greed, David R Thorburn, Trine Tangeraas, Shanti Balasubramaniam, Richard JT Rodenburg
Human Mutation | WILEY | Published : 2020
COX16 is involved in the biogenesis of cytochrome-c-oxidase (complex IV), the terminal complex of the mitochondrial respiratory chain. We present the first report of two unrelated patients with the homozygous nonsense variant c.244C>T(p. Arg82*) in COX16 with hypertrophic cardiomyopathy, encephalopathy and severe fatal lactic acidosis, and isolated complex IV deficiency. The absence of COX16 protein expression leads to a complete loss of the holo-complex IV, as detected by Western blot in patient fibroblasts. Lentiviral transduction of patient fibroblasts with wild-type COX16 complementary DNA rescued complex IV biosynthesis. We hypothesize that COX16 could play a role in the copper delivery..View full abstract
Awarded by Australian National Health and Medical Research Council Fellowship
The authors are very grateful to the patients and their families for their participation. The authors would like to thank the colleagues of the mitochondrial diagnostic group (muscle lab, cell culture lab, and DNA lab) of the Translational Metabolic Laboratory at the Radboud UMC and the Victorian Clinical Genetics Services for excellent technical assistance. The authors would like to acknowledge the Genome Technology Center at the Radboudumc and BGI Copenhagen for technical support of the exome sequencing. Informed consent for diagnostic and research studies was obtained for all subjects in accordance with the Declaration of Helsinki and following the regulations of the local medical ethics committee. Part of this study was supported by an Australian National Health and Medical Research Council Fellowship (1155244 to D. R. T).