A novel variant in COX16 causes cytochrome c oxidase deficiency, severe fatal neonatal lactic acidosis, encephalopathy, cardiomyopathy, and liver dysfunction

Liesbeth T M Wintjes, Maina Kava, Frans A van den Brandt, Mariël A M van den Brand, Oksana Lapina, Yngve T Bliksrud, Mari A Kulseth, Silja S Amundsen, Terje R Selberg, Marion Ybema-Antoine, Omar A Z Tutakhel, Lawrence Greed, David R Thorburn, Trine Tangeraas, Shanti Balasubramaniam, Richard J T Rodenburg

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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.

Original languageEnglish
Pages (from-to)135-141
Number of pages7
JournalHuman mutation
Issue number2
Publication statusPublished - Feb 2021
Externally publishedYes

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