Parkinsonism, premature menopause, and mitochondrial DNA polymerase γ mutations: clinical and molecular genetic study
Abstract
Background Mutations in the gene encoding mitochondrial DNA polymerase gamma (POLG), the enzyme that synthesises mitochondrial DNA (mtDNA), have been associated with a mitochondrial disease-autosomal dominant or recessive progressive external ophthalmoplegia-and multiple deletions of mtDNA. Mitochondrial dysfunction is also suspected to participate in the pathogenesis of Parkinson's disease. However, no primary gene defects affecting mitochondrial proteins causing mendelian transmission of parkinsonism have been characterised. We aimed to analyse the gene sequence of POLG in patients with progressive external ophthalmoplegia and their healthy relatives.Methods In seven families of various ethnic origins we assessed patients with progressive external ophthalmoplegia and unaffected individuals by clinical, biochemical, morphological, and molecular genetic characterisation and positron emission tomography (PET).Findings We recorded mutations in POLG in members of all seven families. Clinical assessment showed significant cosegregation of parkinsonism with POLG mutations (p<0.0001), and PET findings were consistent with dopaminergic neuron loss. Post-mortem examination in two individuals showed loss of pigmented neurons and pigment phagocytosis in substantia nigra without Lewy bodies. Furthermore, most women with progressive external ophthalmoplegia had early menopause-before age 35 years. The POLG gene defect resulted in secondary accumulation of mtDNA deletions in patients' tissues.Interpretation Dysfunction of mitochondrial POLG causes a severe progressive multisystem disorder including parkinsonism and premature menopause, which are not typical of mitochondrial disease. Cosegregation of parkinsonism and POLG mutations in our families suggests that when defective, this gene can underlie mendelian transmission of parkinsonism.Relevance to practice Awareness that mitochondrial POLG mutations can underlie parkinsonism is important for clinicians working in diagnosis of movement disorders, as well as for studies of the genetics of Parkinson's disease. Further, progressive external ophthalmoplegia with muscle weakness and neuropathy can mask symptoms of parkinsonism, and clinicians should pay special attention to detect and treat parkinsonism in those individuals.
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Seven PEO families of various ethnic origins were reported to have Pol γ mutations with multiple mtDNA deletions and reduced mtDNA copy number.
“Seven PEO families of various ethnic origins were reported to have Pol γ mutations with multiple mtDNA deletions (Luoma et al., 2004) and reduced mtDNA copy number (Gui et al., 2015).”
From Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases (2017) · cites this paper as Luoma et al., 2004
The dominant Y955C mutation and two new missense mutations, N468D and A1105T, were discovered in these families.
“The dominant Y955C mutation and two new missense mutations, N468D and A1105T, were discovered in these families (Luoma et al., 2004).”
From Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases (2017) · cites this paper as Luoma et al., 2004
Most of the women in these families had early menopause or primary amenorrhea.
“Most of the women had early menopause or primary amenorrhea.”
From Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases (2017) · cites this paper as Luoma et al., 2004
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- Authors
- Luoma, P., Melberg, A., Rinne, J. O., Kaukonen, J. A., Nupponen, N. N., Chalmers, R. M., Oldfors, A., Rautakorpi, I., Peltonen, L., Majamaa, K., Somer, H., & Suomalainen, A.
- Affiliations
- University of Helsinki (FI)
- Uppsala University Hospital (SE)
- University of Turku (FI)
- National Hospital for Neurology and Neurosurgery (GB)
- Sahlgrenska University Hospital (SE)
- Lapland Central Hospital (FI)
- University of Oulu (FI)
- Venue
- The Lancet
- Publisher
- Elsevier BV
- Published
- 2004-09
- Volume
- 364
- Issue
- 9437
- Pages
- 875-882
- ISSN
- 0099-5355 (ISSN-L)
- 0140-6736
- OpenAlex
- W2130588024
- Cited by
- 548
- References
- 41
- Citations by year
- 2026: 8 · 2025: 9 · 2024: 13 · 2023: 15 · 2022: 23 · 2021: 27 · 2020: 28 · 2019: 18 · 2018: 23 · 2017: 24 · 2016: 31 · 2015: 17 · 2014: 29 · 2013: 32 · 2012: 26
- FWCI
- 21.24
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Lancet (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Sigrid Juséliuksen Säätiö
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Keywords
- parkinsonism, premature menopause, mitochondrial DNA polymerase gamma, POLG mutations, chronic progressive external ophthalmoplegia, mitochondrial disease, mitochondrial DNA deletions, dopaminergic neuron loss, substantia nigra, co-segregation, Mendelian inheritance, Parkinson's disease genetics, movement disorders
- MeSH terms
- DNA Polymerase gamma, Adult, Brain, DNA-Directed DNA Polymerase, DNA, Mitochondrial, Female, Humans, Male, Menopause, Premature, Middle Aged, Mutation, Pedigree, Tomography, Emission-Computed, Ophthalmoplegia, Chronic Progressive External, Sequence Analysis, DNA, Age of Onset, Parkinsonian Disorders
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