MT-ATP6 – Leber hereditary optic neuropathy

MT-ATP6 encodes the a‐subunit of mitochondrial ATP synthase and is maternally inherited. Three probands have been reported with MT-ATP6 variants in Leber hereditary optic neuropathy (LHON): a Russian family with a homoplasmic A9016G change in ATP6 showing 100% penetrance in two affected males (PMID:16050984), and a single patient with a homoplasmic m.8969G>A (p.Ser148Asn) variant presenting LHON-like optic atrophy (PMID:38756953). No additional familial segregation beyond these sibships has been documented.

Functional analyses of MT-ATP6 variants in the context of LHON are limited. The 8527A>G initiation codon mutation (GUG start) had no detectable impact on ATPase subunit a levels, ATP hydrolysis, ATP synthesis, or mitochondrial membrane potential in patient fibroblasts (PMID:14697245). Thus, there is no concordant functional evidence linking MT-ATP6 perturbation to optic neuropathy in these cases.

Overall, the evidence for a causal role of MT-ATP6 in LHON remains Limited: only three probands reported, minimal segregation data, and inconsistent functional support. Additional independent cases and robust mechanistic studies are necessary to confirm MT-ATP6 as a LHON gene.

Key Take-home: Current data do not support routine MT-ATP6 testing for LHON outside research settings.

References

• Mitochondrion • 2005 • A new sequence variant in mitochondrial DNA associated with high penetrance of Russian Leber hereditary optic neuropathy. PMID:16050984
• Biochemical and biophysical research communications • 2004 • GUG is an efficient initiation codon to translate the human mitochondrial ATP6 gene. PMID:14697245
• American journal of ophthalmology case reports • 2024 • Leber's hereditary optic neuropathy like disease in MT-ATP6 variant m.8969G>A. PMID:38756953

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