Identification of a novel homozygous synthesis of cytochrome c oxidase 2 variant in siblings with early-onset axonal Charcot-Marie-Tooth disease.

Human mutation 2022 Apr

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The synthesis of cytochrome c oxidase 2 (SCO2 ) gene encodes for a mitochondrial located metallochaperone essential for the synthesis of the cytochrome c oxidase (COX) subunit 2. Recessive mutations in SCO2 have been reported in several cases with fatal infantile cardioencephalomyopathy with COX deficiency and in only four cases with axonal neuropathy. Here, we identified a homozygous pathogenic variant (c.361G > C; p.[Gly121Arg]) in SCO2 in two brothers with isolated axonal motor neuropathy. To address pathogenicity of the amino acid substitution, biochemical studies were performed and revealed increased level of the mutant SCO2 -protein and dysregulation of COX subunits in leukocytes and moreover unraveled decrease of proteins involved in the manifestation of neuropathies. Hence, our combined data strengthen the concept of SCO2 being causative for a very rare form of axonal neuropathy, expand its molecular genetic spectrum and provide first biochemical insights into the underlying pathophysiology. © 2022 The Authors. Human Mutation published by Wiley Periodicals LLC.

Citation

Andrea Gangfuß, Andreas Hentschel, Nina Rademacher, Albert Sickmann, Burkhard Stüve, Rita Horvath, Claudia Gross, Nicolai Kohlschmidt, Fabian Förster, Angela Abicht, Anne Schänzer, Ulrike Schara-Schmidt, Andreas Roos, Adela Della Marina. Identification of a novel homozygous synthesis of cytochrome c oxidase 2 variant in siblings with early-onset axonal Charcot-Marie-Tooth disease. Human mutation. 2022 Apr;43(4):477-486