MT-CO3 – Mitochondrial Disease

MT-CO3 encodes cytochrome c oxidase subunit III, a core component of mitochondrial respiratory chain complex IV. Pathogenic variants in MT-CO3 disrupt oxidative phosphorylation, leading to multisystem mitochondrial disease (MONDO:0044970).

MT-CO3 variants follow maternal (mitochondrial) inheritance and exhibit heteroplasmic transmission. Heteroplasmic and homoplasmic MT-CO3 mutations have been detected in 179 unrelated patients screened by TTGE and sequencing (PMID:12406974), and in 113 pediatric mitochondrial disease cases (PMID:15466086).

The variant spectrum includes heteroplasmic missense changes such as m.9396G>A (p.Glu64Lys) (PMID:34054915), nonsense mutations like m.9553G>A (p.Trp116Ter) (PMID:33863631), and the 9205delTA microdeletion affecting COX3 processing (PMID:15265003). These alterations occur at varying heteroplasmy levels and can be de novo or maternally inherited.

Functional studies demonstrate that m.9396G>A impairs complex IV assembly and increases reactive oxygen species in cybrid models (PMID:34054915). The 9205delTA mutation reduces COX3 biosynthesis and destabilizes complex IV, resulting in marked cytochrome c oxidase deficiency (PMID:15265003).

The pathogenic mechanism involves defective translation and processing of the MT-CO3 mRNA, leading to complex IV deficiency, reduced ATP synthesis, and lactic acidosis. These findings are concordant between genetic and experimental data and correlate with clinical features such as cardiomyopathy and encephalopathy.

In summary, strong genetic and moderate functional evidence support MT-CO3 as a disease gene for mitochondrial disease. Comprehensive sequencing of MT-CO3, with assessment of heteroplasmy, is essential for accurate diagnosis and management. Key Take-home: MT-CO3 sequencing is clinically useful for diagnosing mitochondrial disease and guiding prognosis in affected individuals.

References

• Clinical Chemistry • 2002 • Comprehensive scanning of the entire mitochondrial genome for mutations. PMID:12406974
• Pediatrics • 2004 • Clinical spectrum, morbidity, and mortality in 113 pediatric patients with mitochondrial disease. PMID:15466086
• Frontiers in Genetics • 2021 • Identification of a Novel Variant in MT-CO3 Causing MELAS. PMID:34054915
• The Biochemical Journal • 2004 • Diminished synthesis of subunit a (ATP6) and altered function of ATP synthase and cytochrome c oxidase due to the mtDNA 9205DeltaTA mutation. PMID:15265003
• Neuromuscular Disorders • 2021 • A novel nonsense variant in MT-CO3 causes MELAS syndrome. PMID:33863631

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