ClinVar

Tiranti et al. (2000) reported an 11-year-old girl with a negative family history and an apparently healthy younger brother. Since 4 years of age, she had developed progressive spastic paraparesis associated with ophthalmoparesis, moderate mental retardation, severe lactic acidosis, and Leigh-like lesions in the putamen. A profound, isolated defect of COX (220110) was found by histochemical and biochemical assays in skin and muscle. Sequence analysis of muscle mtDNA revealed a virtually homoplasmic frameshift mutation in the MTCO3 gene, due to the insertion of an extra C at nucleotide position 9537. Although the 9537insC did not impair transcription of MTCO3, no full-length COX subunit III protein was detected in mtDNA translation assays in vivo. Western blot analysis showed a reduction of specific crossreacting material and the accumulation of early-assembly intermediates of COX, whereas the fully assembled complex was absent. One of these intermediates had an electrophoretic mobility different from those seen in controls, suggesting the presence of a qualitative abnormality of COX assembly. Immunostaining with specific antibodies failed to detect the presence of several smaller subunits in the complex lacking COX subunit III, in spite of the demonstration that these subunits were present in the crude mitochondrial fraction of the patient's cultured fibroblasts. The authors proposed a role for COX subunit III in the incorporation and maintenance of smaller COX subunits within the complex.