MT-CO1 – Mitochondrial Disease

MT-CO1 encodes subunit I of cytochrome c oxidase (Complex IV) and is exclusively maternally inherited. A single proband carrying the c.6498C>A (p.Leu199Ile) variant in MT-CO1 was identified in a Tunisian patient with sensorineural hearing loss, diabetes and congenital visual loss; the variant was absent in 200 controls and is predicted damaging ([PMID:23219819]). No segregation data are available. Broader cohorts of children and adults with biochemical Complex IV deficiency consistently show multi-systemic presentations including encephalopathy, myopathy and hepatomegaly but only rare MT-CO1 point mutations are reported.

Biochemical analyses of skeletal muscle and liver tissues demonstrate reduced mtDNA content, depressed cytochrome c oxidase activity and impaired mitochondrial respiration in patients with mitochondrial disease ([PMID:9700597], [PMID:9303502]). Histochemical staining reveals ragged-red fibers and fiber-type variability concordant with Complex IV deficiency. These data support a mechanism of pathogenicity via impaired oxidative phosphorylation due to MT-CO1 dysfunction.

Key Take-home: MT-CO1 variants can underlie maternal-inherited mitochondrial disease marked by Complex IV deficiency, though evidence remains limited and functional studies are critical for variant interpretation.

References

• Journal of inherited metabolic disease • 1998 • mtDNA depletion and impairment of mitochondrial function in a case of a multisystem disorder including severe myopathy. PMID:9700597
• Biochemical and biophysical research communications • 2013 • A novel MT-CO1 m.6498C>A variation associated with the m.7444G>A mutation in the mitochondrial COI/tRNA(Ser(UCN)) genes in a patient with hearing impairment, diabetes and congenital visual loss. PMID:23219819
• Hepatology (Baltimore, Md.) • 1997 • Defects of the respiratory chain in the normal human liver and in cirrhosis during aging. PMID:9303502

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