POLG2 – Autosomal Dominant Progressive External Ophthalmoplegia

POLG2 encodes the p55 accessory subunit of the mitochondrial DNA polymerase γ holoenzyme, which is critical for processive replication and proofreading of mtDNA. Heterozygous variants in POLG2 have been linked to autosomal dominant progressive external ophthalmoplegia (adPEO), characterized by ptosis, ophthalmoplegia, and multiple mtDNA deletions.

The association was first described in a patient with adPEO and multiple mtDNA deletions harboring the heterozygous c.1105A>G (p.Arg369Gly) variant in POLG2, which showed decreased affinity for the p140 catalytic subunit and impaired polymerase processivity (PMID:22155748).

A recent review identified twelve likely pathogenic heterozygous POLG2 variants across 19 unrelated adult-onset patients with progressive ophthalmoplegia, including segregation of a novel variant in a multigenerational pedigree (PMID:37085601).

In vitro biochemical assays of multiple p55 variants, including p.Arg369Gly, demonstrated reduced stimulation of p140-mediated DNA synthesis and decreased binding affinity (PMID:21555342). Moreover, a p.Gly451Glu heterodimer exhibited dominant-negative interference with wild-type p55, confirming a toxic gain-of-function mechanism (PMID:26123486).

These data support a dominant-negative mechanism by which heterozygous POLG2 variants disrupt polymerase γ holoenzyme stability and processivity, leading to accumulation of mtDNA deletions in muscle and the characteristic adPEO phenotype.

Overall, the gene–disease association is rated Strong based on ~20 unrelated cases, segregation in one family, and concordant functional data. Clinical testing for heterozygous POLG2 variants is recommended for patients presenting with unexplained PEO and mtDNA deletions to confirm diagnosis and guide management.

References

• Mitochondrion • 2012 • A p.R369G POLG2 mutation associated with adPEO and multiple mtDNA deletions causes decreased affinity between polymerase γ subunits PMID:22155748
• Human Molecular Genetics • 2011 • Biochemical analysis of human POLG2 variants associated with mitochondrial disease PMID:21555342
• Human Molecular Genetics • 2015 • POLG2 disease variants: analyses reveal a dominant negative heterodimer, altered mitochondrial localization and impaired respiratory capacity PMID:26123486
• Cerebellum (London, England) • 2024 • POLG2-Linked Mitochondrial Disease: Functional Insights from New Mutation Carriers and Review of the Literature PMID:37085601

Evidence Based Scoring (AI generated)