ATP5F1A – Mitochondrial Disease

ATP5F1A encodes the α-subunit of mitochondrial ATP synthase (complex V), essential for ATP production in oxidative phosphorylation. Pathogenic variants in ATP5F1A result in complex V deficiency manifesting across the mitochondrial disease spectrum, from neonatal encephalopathy to later-onset neurodevelopmental presentations. (MONDO:0044970) is linked to both autosomal recessive and dominant mechanisms with functional concordance in patient cells and model systems.

Two siblings with fatal neonatal encephalopathy harbored a heterozygous c.985C>T (p.Arg329Cys) variant, with maternal allele silencing leading to functional hemizygosity of the mutated allele and severe complex V deficiency in fibroblasts (PMID:23599390). Targeted exome sequencing in 102 patients identified a recessive ATP5F1A mutation modelled in yeast, supporting combined respiratory chain deficiency and recessive inheritance (PMID:23596069). In a cohort of 2,962 individuals with mitochondrial disease and/or dystonia, three unrelated patients had de novo heterozygous ATP5F1A missense variants (c.620G>A (p.Arg207His), c.1037C>T (p.Ser346Phe), c.545G>A (p.Arg182Gln)), demonstrating dominant‐negative or haploinsufficient mechanisms (PMID:34954817).

The variant spectrum includes missense changes affecting intersubunit interfaces and splicing alterations; one recurrent recessive allele was functionally validated in yeast. Segregation analysis shows two affected siblings in one family and multiple de novo events across unrelated probands. Complementation of patient fibroblasts with wild-type ATP5F1A restored complex V assembly and activity, while immunoblotting and oxygen consumption assays confirmed disrupted α/β interaction and reduced ATPase stability. Yeast modeling provided orthogonal evidence for recessive pathogenicity, and proteomic profiling revealed concordant reductions in complex V abundance across samples.

Overall, the clinical validity of the ATP5F1A–mitochondrial disease association is classified as Moderate by ClinGen, supported by six probands across five families and concordant functional studies. Diagnostic sequencing of ATP5F1A should be considered in patients with suspected complex V deficiency or unexplained neonatal encephalopathy. Key Take-home: ATP5F1A variants underlie a clinically actionable form of complex V deficiency with validated functional assays for variant interpretation.

References

• Brain • 2013 • A complex V ATP5A1 defect causes fatal neonatal mitochondrial encephalopathy. PMID:23599390
• Neurology • 2013 • Targeted exome sequencing of suspected mitochondrial disorders. PMID:23596069
• Annals of neurology • 2022 • Variants in Mitochondrial ATP Synthase Cause Variable Neurologic Phenotypes. PMID:34954817

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