POLG – POLG-related Leigh Syndrome

Leigh syndrome is a severe, early-onset neurodegenerative disorder characterized by symmetric necrotic lesions in the basal ganglia and brainstem. Pathogenic biallelic variants in POLG (HGNC:9179), encoding the mitochondrial DNA polymerase γ catalytic subunit, underlie an autosomal recessive form of Leigh syndrome (MONDO:0009723).

Clinical Validity

POLG–Leigh syndrome association is classified as Strong. Fourteen unrelated probands with compound heterozygous or homozygous POLG variants have been reported in independent cohorts (6 children with mtDNA depletion (PMID:18828154), 7 families with Alpers-like encephalopathy (PMID:16896309), and 1 Swedish case with POLG mutations among 25 Leigh syndrome patients (PMID:19103152)). Segregation in multiple families and concordant functional assays demonstrate pathogenicity.

Genetic Evidence

Inheritance is autosomal recessive. A total of 14 probands have been described with biallelic POLG mutations causing Leigh syndrome. The variant spectrum includes missense substitutions (e.g., c.3406G>A (p.Glu1136Lys)), splice‐site and frameshift alleles targeting polymerase and exonuclease domains. No clear founder alleles have been reported. Population frequencies are exceedingly low, consistent with a recessive severe phenotype.

Functional Evidence

Multiple biochemical and in vivo models reveal mechanistic consequences of POLG variants. Polymerase domain mutants (e.g., p.Tyr955Cys, p.Arg943His) show 0.03–30% wild-type activity and decreased fidelity (PMID:15258572). The common A467T mutation impairs accessory‐subunit interaction and reduces catalytic efficiency to 4% of normal (PMID:16024923). Yeast “humanized” models of POLG mutants recapitulate mtDNA depletion and increased mutagenesis, correlating with disease onset (PMID:20185557).

Conflicting Evidence

The G517V variant retains 80–90% polymerase activity and normal subunit interaction in vitro, suggesting it may be a benign polymorphism and not a primary cause of Leigh syndrome (PMID:21856450).

Conclusion

Biallelic POLG mutations cause autosomal recessive Leigh syndrome through loss of polymerase function, mtDNA depletion, and increased genomic instability. Functional studies across multiple systems corroborate genetic findings. Diagnostic testing for POLG variants is warranted in early-onset Leigh syndrome, and biochemical assays can aid variant classification. POLG-related Leigh syndrome should be considered in the differential of infantile mitochondrial encephalopathies.

Key Take-home: POLG loss-of-function variants are a validated cause of autosomal recessive Leigh syndrome and should be included in diagnostic gene panels.

References

• Orphanet Journal of Rare Diseases • 2014 • A multicenter study on Leigh syndrome: disease course and predictors of survival PMID:24731534
• Biochimica et Biophysica Acta • 2009 • MtDNA mutations are a common cause of severe disease phenotypes in children with Leigh syndrome PMID:19103152
• Human Mutation • 2009 • Analysis of mutant DNA polymerase gamma in patients with mitochondrial DNA depletion PMID:18828154
• Journal of Neuropathology and Experimental Neurology • 2006 • POLG1 mutations associated with progressive encephalopathy in childhood PMID:16896309
• Nature Structural & Molecular Biology • 2004 • Structure-function defects of human mitochondrial DNA polymerase in autosomal dominant progressive external ophthalmoplegia PMID:15258572
• The Journal of Biological Chemistry • 2005 • The common A467T mutation in the human mitochondrial DNA polymerase (POLG) compromises catalytic efficiency and interaction with the accessory subunit PMID:16024923
• Human Molecular Genetics • 2010 • mip1 containing mutations associated with mitochondrial disease causes mutagenesis and depletion of mtDNA in Saccharomyces cerevisiae PMID:20185557
• Mitochondrion • 2011 • Biochemical analysis of the G517V POLG variant reveals wild-type like activity PMID:21856450

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