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.

Liesbeth T M Wintjes ¹, Maina Kava ² ³, Frans A van den Brandt ¹, Mariël A M van den Brand ⁴, Oksana Lapina ⁵, Yngve T Bliksrud ⁶, Mari A Kulseth ⁷, Silja S Amundsen ⁷, Terje R Selberg ⁸, Marion Ybema-Antoine ⁴, Omar A Z Tutakhel ¹, Lawrence Greed ⁹, David R Thorburn ¹⁰ ¹¹, Trine Tangeraas ¹², Shanti Balasubramaniam ¹³, Richard J T Rodenburg ¹ ⁴

Affiliations

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.

PMID: 33169484 DOI: 10.1002/humu.24137

Abstract

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.

Keywords

COX16; OXPHOS; assembly factor; cardio-encephalopathy; mitochondrial complex IV deficiency.

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