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ATP5PO encodes a critical subunit of the mitochondrial ATP synthase complex, essential for cellular energy production. Recent studies have identified deleterious variants in ATP5PO in patients with mitochondrial disease (MONDO:0044970), thereby implicating this gene in the pathogenesis of disorders characterized by impaired oxidative phosphorylation (PMID:34954817). Both case‐report and multi‐patient study data support an autosomal recessive mode of inheritance for ATP5PO-related mitochondrial disease.
Genetic evidence includes the identification of biallelic variants in ATP5PO. In one study, an intronic splice-disrupting alteration in compound heterozygosity with a nonsense variant was observed in a patient with mitochondrial disease (PMID:34954817). In a separate report, a homozygous splice variant (c.87+3A>G) was found in three individuals from two unrelated families, further underpinning the role of ATP5PO in mitochondrial dysfunction (PMID:35621276). Together, these findings represent at least four probands with pathogenic variants, which are consistent with autosomal recessive inheritance.
A representative variant reported in association with mitochondrial disease is c.34C>T (p.Gln12Ter), a nonsense alteration that is expected to result in loss-of-function of ATP5PO. The variant spectrum for ATP5PO in mitochondrial disease includes both splice-disrupting and truncating variants, with evidence of recurrence in distinct populations. Although formal segregation data beyond the probands is limited, the genetic findings across independent families greatly strengthen the association.
Functional studies provide additional support for the pathogenicity of ATP5PO variants. Patient fibroblasts harboring these variants demonstrate decreased ATP5PO protein levels, defective assembly of complex V, and markedly reduced ATPase activity. Complementary assays, including proteomic analysis and enzymatic activity measurements, have consistently shown that the functional impairment of ATP synthase correlates with the clinical phenotype, confirming the deleterious impact of these variants (PMID:35621276) (PMID:8106529).
No significant conflicting evidence has been reported to dispute the association between ATP5PO and mitochondrial disease. While some studies have described heterogeneity in the overall clinical presentation, the convergence of genetic and functional data supports that disruption of ATP5PO impairs mitochondrial function, leading to the disease phenotype. The experimental data from both cellular and biochemical assays are in full concordance with the observed clinical features.
In summary, strong genetic evidence from four probands combined with robust functional assessments establishes ATP5PO as a causative gene for mitochondrial disease. The findings support the use of ATP5PO variant testing in the diagnostic evaluation of patients with suspected mitochondrial dysfunction, thereby providing high clinical utility in genomic medicine.
Gene–Disease AssociationStrongAt least four unrelated probands identified with biallelic ATP5PO variants (PMID:35621276; PMID:34954817) and corroborated by functional assays. Genetic EvidenceStrongMultiple variant types (nonsense and splice-disrupting) have been reported in independent families, supporting autosomal recessive inheritance with consistent clinical presentation. Functional EvidenceModerateRobust in vitro assays, including decreased protein levels, defective complex V assembly, and reduced ATPase activity, have been demonstrated in patient samples. |