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

Change log
Hentschel, Andreas 
Rademacher, Nina 
Sickmann, Albert 
Stüve, Burkhard 

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.


Funder: European Regional Development Fund (ERDF); Id:

Funder: Regierenden Bürgermeister von Berlin ‐ Senatskanzlei Wissenschaft und Forschung

Funder: Bundesministerium für Bildung und Forschung; Id:

Funder: Ministerium für Kultur und Wissenschaft des Landes Nordrhein‐Westfalen; Id:

Charcot-Marie-Tooth disease, axonal neuropathy, synthesis of cytochrome c oxidase 2 (SCO2), white blood cell proteomics, Carrier Proteins, Charcot-Marie-Tooth Disease, Electron Transport Complex IV, Humans, Male, Mitochondrial Proteins, Molecular Chaperones, Mutation, Oxidoreductases, Siblings
Journal Title
Hum Mutat
Conference Name
Journal ISSN
Volume Title
Hindawi Limited
Leibniz‐Research‐Cluster (031A360E)