MT-ATP6 – Maternally Inherited Leigh Syndrome

Pathogenic variants in the mitochondrial MT-ATP6 gene (HGNC:7414) are a well-established cause of maternally inherited Leigh syndrome (MILS) (MONDO:0016814). MT-ATP6 encodes subunit a of the mitochondrial F₁F₀-ATP synthase complex (complex V), essential for oxidative phosphorylation. Disease typically follows maternal inheritance with heteroplasmic or homoplasmic missense changes that impair ATP synthesis, leading to neurodegeneration, ataxia, seizures, and characteristic brain lesions.

Genetic evidence supports a definitive gene–disease relationship. Maternal transmission of the m.8993T>G (c.8993T>G (p.Leu156Arg)) and m.8993T>C (p.Leu156Pro) variants has been documented in over 200 probands across multiple unrelated maternal lineages ([PMID:30763462]). Segregation of the m.8993T>C variant with clinical MILS in at least three affected maternal relatives confirms consistent inheritance patterns ([PMID:22819295]).

Variant spectrum is dominated by missense changes in the MT-ATP6 coding sequence. The canonical m.8993T>G (p.Leu156Arg) variant is recurrent, often near-homoplasmic in affected tissues. Additional pathogenic alleles include T9185C (p.Leu220Pro) and T9191C (p.Leu222Pro), each showing high heteroplasmy in symptomatic individuals. No large deletions or deep-intronic MT-ATP6 variants have been implicated in MILS to date.

Functional studies demonstrate a clear mechanistic basis for pathogenicity. The T8993G/C mutations impair ATP synthase turnover by 60–70%, destabilize the F₁F₀ complex despite normal assembly, and compromise proton coupling across the inner membrane ([PMID:17121862]). Primary fibroblasts harboring m.8993T>G exhibit defective oxidative phosphorylation, reduced spare respiratory capacity, and energy crisis under stress ([PMID:29602698]). Antioxidant treatment partially rescues ATP production in patient cells ([PMID:14998933]).

Some mitochondrial DNA variants in MT-ATP6 show limited or no functional impact. For example, the rare A9115G substitution identified alongside an MT-ND1 variant exhibited no measurable bioenergetic defect in cybrid studies ([PMID:17320116]). Such findings underscore the need for combined genetic and functional assessment when interpreting novel MT-ATP6 changes.

Integration of extensive genetic and experimental data establishes MT-ATP6 as definitively associated with maternally inherited Leigh syndrome. Diagnosis relies on mtDNA sequencing and heteroplasmy quantification in affected tissues. Functional assays of complex V activity can confirm pathogenicity for variants of uncertain significance. Key take-home: MT-ATP6 sequencing is clinically actionable for confirming MILS, guiding family counseling, and informing potential antioxidant therapies.

References

• Molecular genetics and metabolism • 2012 • Whole mitochondrial genome analysis of a family with NARP/MILS caused by m.8993T>C mutation in the MT-ATP6 gene. PMID:22819295
• Human molecular genetics • 2004 • The mtDNA T8993G (NARP) mutation results in an impairment of oxidative phosphorylation that can be improved by antioxidants. PMID:14998933
• The Journal of biological chemistry • 2007 • ATP6 homoplasmic mutations inhibit and destabilize the human F1F0-ATP synthase without preventing enzyme assembly and oligomerization. PMID:17121862
• Molecular genetics and metabolism • 2018 • Novel insights into the functional metabolic impact of an apparent de novo m.8993T>G variant in the MT-ATP6 gene associated with maternally inherited form of Leigh Syndrome. PMID:29602698
• Human mutation • 2019 • MT-ATP6 mitochondrial disease variants: Phenotypic and biochemical features analysis in 218 published cases and cohort of 14 new cases. PMID:30763462

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