A novel nonsense variant in MT-COX3 causes MELAS syndrome

Abstract Both mitochondrial and nuclear gene mutations can cause cytochrome c oxidase (COX, complex Ⅳ) dysfunction, leading to mitochondrial diseases. However, although numerous diseases resulted from the defects of the COX subunit or other COX assembly factors have been documented, clinical cases directly related to mitochondrial cytochrome c oxidase subunit 3 gene (MT-COX3) mutations are relatively rare. Here, we report a 47-year-old female patient presented with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome. Muscle pathology revealed ragged-red fibres (RRFs) and remarkable COX-deficient (COX-def) muscle fibres. Muscle mitochondrial DNA (mtDNA) sequencing analysis identified a novel MT-COX3 variant (m.9553G>A) that changed a highly conserved amino acid to a stop codon (p.Trp116*). This variant was heteroplasmic in multiple tissues, where the mutation load was 13% in oral epithelial cells, 89% in muscle samples, and not detectable in the peripheral blood lymphocytes. Single muscle fibre PCR analysis showed clear segregation of the mutation load with COX-def fibres. Western blot analysis of the muscle samples revealed a significant decrease in the levels of COX1, COX2, COX3, COX4 and UQCRC2. COX respiration activity was remarkably reduced (58.84%) relative to the controls according to spectrophotometric assays. Taken together, our results indicated that this m.9553G>A variant may be responsible for the MELAS symdrome in the proband by affecting the stability and function of COX. The study expands the clinical and molecular spectrum of COX3-specific mitochondrial diseases.