Background: The POLG1 gene encodes the catalytic subunit of DNA polymerase gamma, essential for mitochondrial DNA replication and repair. Mutations in POLG1 have been linked to a spectrum of clinical phenotypes, and may account for up to 25% of all adult presentations of mitochondrial disease.
Methods and results: We present 14 patients, with characteristic features of mitochondrial disease including progressive external ophthalmoplegia (PEO) and Alpers–Huttenlocher syndrome and laboratory findings indicative of mitochondrial dysfunction, including cytochrome c oxidase (COX) deficiency and multiple deletions or depletion of the mitochondrial DNA. Four novel POLG1 missense substitutions (p.R597W, p.L605R, p.G746S, p.A862T), are described, together with the first adult patient with a recently described polymerase domain mutation (p.R1047W). All novel changes were rare in a control population and affected highly conserved amino acids.
Conclusion: The addition of these substitutions—including the first report of a dinucleotide mutation (c.1814_1815TT>GC)—to the growing list of defects further confirms the importance of POLG1 mutations as the underlying abnormality in a range of neurological presentations.
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Competing interests: None.
Funding: PFC is a Wellcome Trust Senior Fellow in Clinical Science who also receives funding from the United Mitochondrial Diseases Foundation, an unconditional research grant from the US Army, The Parkinson’s Disease Society, and the EU FP6 program EUmitocombat and MITOCIRCLE. RWT and DMT acknowledge the Wellcome Trust, the Muscular Dystrophy Campaign, the Newcastle upon Tyne Hospitals Foundation NHS Trust and the Department of Health (NCG Rare Mitochondrial Disorders of Adults and Children Service) for their continuing financial support.
Ethics approval: This study was performed under the ethical guidelines issued by each of our institutions for clinical studies
Patient consent: Obtained