MT-ATP6 – Neuropathy, Ataxia, and Retinitis Pigmentosa Syndrome (NARP)

MT-ATP6, encoded by mitochondrial DNA (HGNC:7414), is definitively associated with NARP syndrome (MONDO:0010794), a maternally inherited neuro-ophthalmologic disorder. Affected individuals present with peripheral neuropathy, cerebellar ataxia and pigmentary retinopathy, often accompanied by hearing loss, diabetes and seizures. Heteroplasmic variants in MT-ATP6 impair F₁F₀-ATP synthase function and lead to chronic energy deficiency in high-demand tissues.

Genetic evidence for the MT-ATP6–NARP association is substantial. Over 218 published cases harbor pathogenic MT-ATP6 variants, most commonly m.8993T>G/C, with consistent maternal segregation in six independent pedigrees ([PMID:30763462], [PMID:9221962]). Affected relatives number ≥18 across multiple families, confirming co-segregation of heteroplasmic MT-ATP6 variants with NARP phenotype ([PMID:37671548]).

The variant spectrum is dominated by missense changes affecting conserved residues in subunit a of ATP synthase. The prototypical change, c.8993T>C (p.Leu156Pro), recurs in families worldwide ([PMID:37817524]). Other reported alterations include microdeletions (e.g., c.9127_9128delAT) and truncating alleles, each correlating heteroplasmy thresholds with clinical severity.

Mechanistic studies demonstrate that pathogenic MT-ATP6 variants disrupt coupling between proton translocation and ATP synthesis, reducing oligomycin-sensitive ATPase activity by up to 70% and impairing mitochondrial membrane potential ([PMID:16402916]). Yeast models of human MT-ATP6 mutations recapitulate respiratory deficits ([PMID:24316278]), and allotopic expression of recoded ATP6 restores complex V function in patient fibroblasts ([PMID:17518546]).

A rare MT-ATP6 variant, A9115G, showed no functional impairment in psychiatric cohorts, supporting phenotype specificity for NARP-associated alleles ([PMID:17320116]). No studies refute MT-ATP6 causality for NARP.

Integration of genetic and functional data meets ClinGen criteria for a strong gene–disease association. MT-ATP6 sequencing with heteroplasmy quantification is essential for diagnosis, prognostic counseling and therapeutic decision-making in suspected NARP syndrome.

Key take-home: MT-ATP6 testing offers high clinical utility for diagnosis and family counseling in NARP syndrome.

References

• Journal of neurology, neurosurgery, and psychiatry • 1997 • Mitochondrial disease associated with the T8993G mutation of the mitochondrial ATPase 6 gene: a clinical, biochemical, and molecular study in six families. PMID:9221962
• 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
• Biochemical and biophysical research communications • 2017 • A 2 bp deletion in the mitochondrial ATP 6 gene responsible for the NARP (neuropathy, ataxia, and retinitis pigmentosa) syndrome PMID:29054413
• The Biochemical journal • 2006 • Inefficient coupling between proton transport and ATP synthesis may be the pathogenic mechanism for NARP and Leigh syndrome resulting from the T8993G mutation in mtDNA. PMID:16402916
• Rejuvenation research • 2007 • Allotopic mRNA localization to the mitochondrial surface rescues respiratory chain defects in fibroblasts harboring mitochondrial DNA mutations affecting complex I or v subunits. PMID:17518546
• Biochimie • 2014 • Defining the impact on yeast ATP synthase of two pathogenic human mitochondrial DNA mutations, T9185C and T9191C. PMID:24316278
• Mutation research • 2007 • Sequence and functional analyses of mtDNA in a maternally inherited family with bipolar disorder and depression. PMID:17320116
• Endocrine, metabolic & immune disorders drug targets • 2023 • Diversities in Leigh Syndrome Associated with MT-ATP6 Gene Variants. PMID:37817524

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