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A novel variant in COX16 causes cytochrome c oxidase deficiency, severe fatal neonatal lactic acidosis, encephalopathy, cardiomyopathy, and liver dysfunction
Author(s) -
Wintjes Liesbeth T. M.,
Kava Maina,
Brandt Frans A.,
Brand Mariël A. M.,
Lapina Oksana,
Bliksrud Yngve T.,
Kulseth Mari A.,
Amundsen Silja S.,
Selberg Terje R.,
YbemaAntoine Marion,
Tutakhel Omar A. Z.,
Greed Lawrence,
Thorburn David R.,
Tangeraas Trine,
Balasubramaniam Shanti,
Rodenburg Richard J. T.
Publication year - 2021
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.24137
Subject(s) - lactic acidosis , biology , cytochrome c oxidase , encephalopathy , sulfite oxidase , respiratory chain , mitochondrion , medicine , endocrinology , genetics , biochemistry , enzyme
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.