Identification of a homozygous SCO2 variant in two siblings strengthens the concept of this gene being causative for early-onset axonal Charcot-Marie-Tooth neuropathy

ABSTRACT: The mitochondrial resident SCO2 protein acts as a copper metallochaperone essential for the synthesis and maturation of cytochrome c oxidase subunit II (MT-CO2/COX2). Recessive mutations in the synthesis of cytochrome C oxidase 2 gene SCO2 were reported in several cases with fatal infantile cardioencephalomyopathy associated with COX deficiency and in four cases with axonal neuropathy. Further confirming the phenotypic spectrum, we identified a homozygous variant (c.361G>C; p.(Gly121Arg)) in SCO2 in two brothers with axonal motor neuropathy. In contrast to most cases, our patients developed exclusively a motor neuropathy, and especially did not present with cardiomyopathy (leading to death in early infancy). Based on the classification of the detected amino acid substitution p.(Gly121Arg) as a variant of uncertain significance (VUS3), further studies toward a robust validation were carried out: results of segregation analysis showed homozygosity only in the two index patients but not in the healthy siblings. Protein studies including proteomic profiling showed an effect on the proteomic signature and accord with a pathogenic character of the amino acid substitution impacting on COX subunit assembly with a profound decrease of subunit II as well as on the homeostasis of proteins beyond mitochondria including such belonging to endocytic processes and opioid uptake. Hence, our combined studies strengthen the concept of SCO2 being causative for early-onset axonal Charcot-Marie-Tooth neuropathy, extend the mutational spectrum associated with this phenotype by introducing the first causative homozygous variant and provide first biochemical insights into the etiopathology.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Leukocyte

SUBMITTER: Andreas Hentschel  

LAB HEAD: Andreas Hentschel

PROVIDER: PXD026283 | Pride | 2024-05-22

REPOSITORIES: Pride