A novel m.5906G > a variant in MT-CO1 causes MELAS/Leigh overlap syndrome.

The MELAS/Leigh overlap syndrome manifests with a blend of clinical and radiographic traits from both MELAS and LS. However, the association of MELAS/Leigh overlap syndrome with MT-CO1 gene variants has not been previously reported. In this study, we report a patient diagnosed with MELAS/Leigh overlap syndrome harboring the m.5906G > A variant in MT-CO1, with biochemical evidence supporting the pathogenicity of the variant. The variant m.5906G > A that led to a synonymous variant in the start codon of MT-CO1 was filtered as the candidate disease-causing variant of the patient. Patient-derived fibroblasts were used to generate a series of monoclonal cells carrying different m.5906G > A variant loads for further functional assays. The oxygen consumption rate, ATP production, mitochondrial membrane potential and lactate assay indicated an impairment of cellular bioenergetics due to the m.5906G > A variant. Blue native PAGE analysis revealed that the m.5906G > A variant caused a deficiency in the content of mitochondrial oxidative phosphorylation complexes. Furthermore, molecular biology assays performed for the pathogenesis, mtDNA copy number, mtDNA-encoded subunits, and recovery capacity of mtDNA were all deficient due to the m.5906G > A variant, which might be caused by mtDNA replication deficiency. Overall, our findings demonstrated the pathogenicity of m.5906G > A variant and proposed a potential pathogenic mechanism, thereby expanding the genetic spectrum of MELAS/Leigh overlap syndrome.