A novel variant in COX16 causes cytochrome c oxidase deficiency, severe fatal neonatal lactic acidosis, encephalopathy, cardiomyopathy, and liver dysfunction
- Hum Mutat. 2021 Feb;42(2):135-141. doi: 10.1002/humu.24137.
- 1. Department of Laboratory Medicine, Translational Metabolic Laboratory, Radboud Centre for Mitochondrial Medicine, Radboudumc, Nijmegen, The Netherlands.
- 2. Department of Neurology, Perth Children's Hospital, Perth, Western Australia, Australia.
- 3. School of Pediatrics and Child Health, University of Western Australia, Perth, Western Australia, Australia.
- 4. Department of Pediatrics, Radboud Centre for Mitochondrial Medicine, Radboudumc, Nijmegen, The Netherlands.
- 5. Department for Radiology and Nuclear Medicine, Oslo University Hospital, Oslo, Norway.
- 6. Norwegian National Unit for Diagnostics of Congenital Metabolic Disorders, Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway.
- 7. Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
- 8. Department of Pediatrics, Ostfold Hospital Trust, Kalnes, Norway.
- 9. Department of Clinical Biochemistry, PathWest, Perth, Western Australia, Australia.
- 10. Murdoch Children's Research Institute and Victorian Clinical Genetics Services, Royal Children's Hospital, Melbourne, Victoria, Australia.
- 11. Department of Pediatrics, University of Melbourne, Melbourne, Victoria, Australia.
- 12. Norwegian National Unit for Newborn Screening, Division of Pediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway.
- 13. Western Sydney Genetics Program, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.
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 route of the COX2 module as part of the complex IV assembly. Our data provide clear evidence for the pathogenicity of the COX16 variant as a cause for the observed clinical features and the isolated complex IV deficiency in these two patients and that COX16 deficiency is a cause for mitochondrial disease.