ArticleHuman molecular genetics2019
Structural basis for adPEO-causing mutations in the mitochondrial TWINKLE helicase.
Article in Human molecular genetics, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 23 citations in OpenAlex.
- Structural and single-molecule insights into the core human mitochondrial DNA replisome.The Biochemical journal · 2026Review
- Human mitochondrial helicase Twinkle has RNA binding, annealing, and strand-exchange activities.Nucleic acids research · 2026Article
- Single-molecule fluorescence reveals the DNA unwinding mechanism of mitochondrial helicase TWINKLE and its interplay with single-stranded DNA-binding proteins.Nucleic acids research · 2025Article
- A Case Report of Auditory Neuropathy Due to TWNK Gene Mutations.The journal of international advanced otology · 2025Review
- Identification of genetic mechanisms of non-isolated auditory neuropathy with various phenotypes in Chinese families.Orphanet journal of rare diseases · 2025Article
- Twinkle-Catalyzed Toehold-Mediated DNA Strand Displacement Reaction.Journal of the American Chemical Society · 2023Article
- Structural and Molecular Basis for Mitochondrial DNA Replication and Transcription in Health and Antiviral Drug Toxicity.Molecules (Basel, Switzerland) · 2023Review
- The N-terminal domain of human mitochondrial helicase Twinkle has DNA-binding activity crucial for supporting processive DNA synthesis by polymerase γ.The Journal of biological chemistry · 2023Article
- Structural and dynamic basis of DNA capture and translocation by mitochondrial Twinkle helicase.Nucleic acids research · 2022Article
- Method for the structural analysis of Twinkle mitochondrial DNA helicase by cryo-EM.Methods (San Diego, Calif.) · 2022Article
- Structural insight and characterization of human Twinkle helicase in mitochondrial disease.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Mitochondrial protein dysfunction in pathogenesis of neurological diseases.Frontiers in molecular neuroscience · 2022Review
- A Novel Missense Mutation inPharmacogenomics and personalized medicine · 2022Article
- Single-molecule level structural dynamics of DNA unwinding by human mitochondrial Twinkle helicase.The Journal of biological chemistry · 2020Article
- Review
- History of DNA Helicases.Genes · 2020Review
- Perrault syndrome with neurological features in a compound heterozygote for two TWNK mutations: overlap of TWNK-related recessive disorders.Journal of translational medicine · 2019Article
- Organization of DNA in Mammalian Mitochondria.International journal of molecular sciences · 2019Review
Corrections and comments
- Erratum issued
Authors and funding
5 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
TWINKLE is the helicase involved in replication and maintenance of mitochondrial DNA (mtDNA) in mammalian cells. Structurally, TWINKLE is closely related to the bacteriophage T7 gp4 protein and comprises a helicase and primase domain joined by a flexible linker region. Mutations in and around this linker region are responsible for autosomal dominant progressive external ophthalmoplegia (adPEO), a neuromuscular disorder associated with deletions in mtDNA. The underlying molecular basis of adPEO-causing mutations remains unclear, but defects in TWINKLE oligomerization are thought to play a major role. In this study, we have characterized these disease variants by single-particle electron microscopy and can link the diminished activities of the TWINKLE variants to altered oligomeric properties. Our results suggest that the mutations can be divided into those that (i) destroy the flexibility of the linker region, (ii) inhibit ring closure and (iii) change the number of subunits within a helicase ring. Furthermore, we demonstrate that wild-type TWINKLE undergoes large-scale conformational changes upon nucleoside triphosphate binding and that this ability is lost in the disease-causing variants. This represents a substantial advancement in the understanding of the molecular basis of adPEO and related pathologies and may aid in the development of future therapeutic strategies.
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