Cytochrome <i>c</i> Oxidase subunit I microdeletion in a patient with motor neuron disease

TLDR

A heteroplasmic 5‑bp microdeletion in the mitochondrial COX I gene, causing premature termination, was identified in a patient with severe muscle COX deficiency and motor neuron‑like degeneration, suggesting a link between OXPHOS dysfunction and motor neuron disease. The mutation produced a COX holoenzyme assembly defect, with reduced subunits II–IV and a strong correlation between mutation load and COX I loss, and was associated with an atypical isolated motor neuron disease phenotype, implying that OXPHOS impairment may contribute to some MND cases.

Abstract

Abstract An out‐of‐frame mutation of the mitochondrial DNA‐encoded subunit I of cytochrome c oxidase (COX) was discovered during investigation of a severe isolated muscle COX deficiency in a patient with motor neuron‐like degeneration. The mutation is a heteroplasmic 5‐bp microdeletion located in the 5′ end of the COI gene, leading to premature termination of the corresponding translation product. Western blot analysis, immunohistochemistry, and single‐fiber polymerase chain reaction demonstrated a tight correlation between COX defect, COX I expression, and percentage of mutation. COX subunits II, III, and IV were decreased as well, suggesting a defective assembly of COX holoenzyme. The mutation was associated with a clinical phenotype unusual for a mitochondrial disorder, that is, an isolated motor neuron disease(MND) with some atypical findings, including early onset, preferential involvement of the upper motor neuron, and increased cerebrospinal fluid protein content. MND may arise from impaired scavenging and overproduction of free oxygen radicals, a by‐product of oxidative phosphorylation (OXPHOS). Our observation suggests that OXPHOS impairment could play a role in the pathogenesis of some MND cases.