A Novel Variant in COX16 Causes Cytochrome c Oxidase Deficiency, Severe Fatal Neonatal Lactic Acidosis, Encephalopathy, Cardiomyopathy and Liver Dysfunction.

COX16 is involved in the biogenesis of cytochrome-c-oxidase (complex IV), the terminal complex of the mitochondrial respiratory chain (RC). 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 cDNA 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. This article is protected by copyright. All rights reserved.