Can the MT-CO2 gene surprise us with something? – A review of variants considered as pathogenic by identifying conserved sites

Background

Cytochrome oxidase subunit II is encoded by the MT-CO2 gene and belongs to a large internal membrane complex called cytochrome c oxidase. To date, no pathogenic single nucleotide variant has been confirmed in this gene according to the MITOMAP database. The goal of this study was to review the literature and attempt to interpret all defined variants of the MT-CO2 gene, either directly associated with symptoms or only by the occurrence of variant in specific diseases.

Methods

Available databases were searched for clinically relevant variants in the MT-CO2 gene. Variant interpretation was based on HelixMTdb frequency, identification of conserved sites in primates, particularly Pan paniscus and Pan troglodytes sequences from GenBank, MITOMAP data and the status of the Predict program.

Results

We found 23 single nucleotide variants in 30 papers where the authors suspected or directly linked variants with a specific phenotype. The most common method sequencing method was Sanger sequencing in 17 papers, and the next-generation sequencing in 6 papers.

Conclusions

Only two potentially pathogenic variants m.8163A > G and m.7887G > A were found, meeting almost all the restrictive criteria for confirmed mitochondrial pathogenic variants. Unfortunately, none of the variants described in all of the papers/databases analysed can be unquestionably classified as pathogenic. Considering that this is a critical respiratory chain subunit gene, further research is needed.