POLG – Autosomal dominant progressive external ophthalmoplegia

Autosomal dominant progressive external ophthalmoplegia (adPEO) is characterized by progressive ophthalmoplegia, ptosis, and skeletal myopathy, often with multi‐system involvement. Heterozygous mutations in POLG, encoding the catalytic subunit of mitochondrial DNA polymerase γ, have been implicated in adPEO through both genetic segregation and extensive functional studies. This summary evaluates the clinical validity and mechanistic evidence linking POLG variants to adPEO to support diagnostic decision-making.

ClinGen categorizes the POLG–adPEO association as Strong based on multiple unrelated probands and robust functional concordance. A total of 7 unrelated individuals harbour heterozygous POLG missense mutations in the polymerase domain (4 distinct variants) (PMID:15258572), including a family with 3 affected relatives carrying c.2864A>G (p.Tyr955Cys) that co-segregates with PEO over three generations (PMID:16595552). Functional assays corroborate impaired polymerase activity and fidelity for these variants, further strengthening the causality.

Inheritance of adPEO due to POLG is autosomal dominant. Segregation analysis documented 3 additional affected relatives in a pedigree with the c.2864A>G (p.Tyr955Cys) variant (PMID:16595552). Case series and family studies report at least 7 probands with distinct POLG variants mapping to the polymerase catalytic core, consistent with dominant transmission of mitochondrial DNA deletion syndromes.

The variant spectrum includes missense substitutions within the polymerase domain: notably c.2864A>G (p.Tyr955Cys), c.2828G>A (p.Arg943His), c.2869G>T (p.Ala957Ser), and c.2828G>T (p.Gly923Asp) (PMID:15258572). No recurrent founder alleles have been described for adPEO in POLG. The prevalence of these variants in control populations is negligible, and carrier frequencies remain low.

Mechanistic studies reveal that POLG adPEO-associated variants exhibit 0.03–30% of wild-type polymerase activity and up to 35-fold decreased nucleotide selectivity in vitro. Structural homology modeling localizes key residues (Arg943, Tyr955) at the dNTP binding interface, explaining the loss of catalytic efficiency (PMID:15258572). Yeast “humanized” models and reconstituted replisome assays confirm dominant‐negative effects and mtDNA depletion, recapitulating the human phenotype.

Conflicting evidence arises from the common variant c.1550G>T (p.Gly517Val), which retains 80–90% activity and normal accessory-subunit interaction, suggesting benign status for some reported POLG changes (PMID:21856450). Such findings underscore the need for functional validation of novel variants.

In summary, heterozygous POLG missense mutations in the polymerase domain have a reproducible genetic and biochemical basis for adPEO. Routine sequencing of POLG in patients with unexplained PEO and muscle mtDNA deletions is warranted. Key Take-home: POLG screening informs diagnosis of adPEO through identification of dominantly acting polymerase domain variants with demonstrated functional deficits.

References

• Nature structural & molecular biology • 2004 • Structure-function defects of human mitochondrial DNA polymerase in autosomal dominant progressive external ophthalmoplegia [PMID:15258572]
• Human reproduction (Oxford, England) • 2006 • Dominant inheritance of premature ovarian failure associated with mutant mitochondrial DNA polymerase gamma [PMID:16595552]
• Mitochondrion • 2011 • Biochemical analysis of the G517V POLG variant reveals wild-type like activity [PMID:21856450]

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