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URL of this page: https://medlineplus.gov/genetics/gene/twnk/

TWNK gene

twinkle mtDNA helicase

Normal Function

The TWNK gene provides instructions for making a protein called Twinkle. This protein is found in mitochondria, which are structures that convert the energy from food into a form that cells can use.

Mitochondria each contain a small amount of DNA, known as mitochondrial DNA (mtDNA), which is essential for the normal function of these structures. The Twinkle protein is involved in the production and maintenance of mtDNA. It functions as a helicase, which means it binds to DNA and temporarily unwinds the two spiral strands (double helix) of the DNA molecule. This unwinding is necessary for copying (replicating) mtDNA when new mitochondria are made.

The TWNK gene can also produce other versions (isoforms) of the protein. One of these iosforms is called Twinky and is shorter than Twinkle. The functions of these isoforms are unclear.

Health Conditions Related to Genetic Changes

Ataxia neuropathy spectrum

Genetic changes that cause disease are called pathogenic variants. Pathogenic variants in the TWNK gene have been found in a small number of people with ataxia neuropathy spectrum. This condition is characterized by loss of coordination (ataxia) and abnormal nerve function (neuropathy). Many affected individuals also have severe brain dysfunction (encephalopathy) with seizures.

Pathogenic variants in the TWNK gene disrupt the function of Twinkle, causing problems during mtDNA replication. As a result, large sections of mtDNA are deleted, which impairs normal mitochondrial function. Tissues that require large amounts of energy, like the brain and muscles, are particularly sensitive to these changes, leading to the signs and symptoms of ataxia neuropathy spectrum.

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Infantile-onset spinocerebellar ataxia

Pathogenic variants in the TWNK gene have been found to cause infantile-onset spinocerebellar ataxia (IOSCA). This disorder primarily affects the nervous system. Individuals with IOSCA have a short period of normal development, then they begin to experience movement problems, neuropathy, and other signs and symptoms that typically worsen over time.

The TWNK gene variants that cause IOSCA impair or reduce the function of the Twinkle protein. As a result, mtDNA cannot be replicated efficiently, which reduces the amount of mtDNA (mtDNA depletion). A decrease in the amount of mtDNA impairs mitochondrial function, especially in the nervous system, and leads to the neurological dysfunction and other problems associated with IOSCA.

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Perrault syndrome

Pathogenic variants in the TWNK gene are a rare cause of Perrault syndrome. Perrault syndrome is characterized by hearing loss, neuropathy, ataxia, and abnormalities of the ovaries. Researchers predict that TWNK gene variants impair the protein's ability to act as a helicase. This reduces mitochondrial function and leads to the signs and symptoms of Perrault syndrome.

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Progressive external ophthalmoplegia

Pathogenic variants in the TWNK gene have been identified in people with an eye condition called progressive external ophthalmoplegia. This disorder weakens the muscles that control eye movement and causes the eyelids to droop (ptosis).

Pathogenic variants in the TWNK gene disrupt the function of Twinkle, causing problems with mtDNA replication. As a result, large sections of mtDNA are deleted, which impairs normal mitochondrial function. Eye muscles are especially dependent on mitochondria for energy and are particularly sensitive to these changes, leading to the signs and symptoms of progressive external ophthalmoplegia.

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Other Names for This Gene

  • C10orf2
  • chromosome 10 open reading frame 2
  • FLJ21832
  • PEO
  • PEO1
  • T7 gp4-like protein with intramitochondrial nucleoid localization
  • TWINKLE
  • TWINL

Additional Information & Resources

Tests Listed in the Genetic Testing Registry

Scientific Articles on PubMed

Catalog of Genes and Diseases from OMIM

Gene and Variant Databases

References

  • Bermejo-Guerrero L, de Fuenmayor-Fernandez de la Hoz CP, Serrano-Lorenzo P, Blazquez-Encinar A, Gutierrez-Gutierrez G, Martinez-Vicente L, Galan-Davila L, Garcia-Garcia J, Arenas J, Muelas N, Hernandez-Lain A, Dominguez-Gonzalez C, Martin MA. Clinical, Histological, and Genetic Features of 25 Patients with Autosomal Dominant Progressive External Ophthalmoplegia (ad-PEO)/PEO-Plus Due to TWNK Mutations. J Clin Med. 2021 Dec 22;11(1):22. doi: 10.3390/jcm11010022. Citation on PubMed
  • El-Hattab AW, Craigen WJ, Wong LJC, Scaglia F. Mitochondrial DNA Maintenance Defects Overview. 2018 Mar 8. In: Adam MP, Bick S, Mirzaa GM, Wallace SE, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from http://www.ncbi.nlm.nih.gov/books/NBK487393/ Citation on PubMed
  • Fratter C, Gorman GS, Stewart JD, Buddles M, Smith C, Evans J, Seller A, Poulton J, Roberts M, Hanna MG, Rahman S, Omer SE, Klopstock T, Schoser B, Kornblum C, Czermin B, Lecky B, Blakely EL, Craig K, Chinnery PF, Turnbull DM, Horvath R, Taylor RW. The clinical, histochemical, and molecular spectrum of PEO1 (Twinkle)-linked adPEO. Neurology. 2010 May 18;74(20):1619-26. doi: 10.1212/WNL.0b013e3181df099f. Citation on PubMed or Free article on PubMed Central
  • Hakonen AH, Goffart S, Marjavaara S, Paetau A, Cooper H, Mattila K, Lampinen M, Sajantila A, Lonnqvist T, Spelbrink JN, Suomalainen A. Infantile-onset spinocerebellar ataxia and mitochondrial recessive ataxia syndrome are associated with neuronal complex I defect and mtDNA depletion. Hum Mol Genet. 2008 Dec 1;17(23):3822-35. doi: 10.1093/hmg/ddn280. Epub 2008 Sep 5. Citation on PubMed
  • Johnson LC, Singh A, Patel SS. The N-terminal domain of human mitochondrial helicase Twinkle has DNA-binding activity crucial for supporting processive DNA synthesis by polymerase gamma. J Biol Chem. 2023 Jan;299(1):102797. doi: 10.1016/j.jbc.2022.102797. Epub 2022 Dec 14. Citation on PubMed
  • Korhonen JA, Pande V, Holmlund T, Farge G, Pham XH, Nilsson L, Falkenberg M. Structure-function defects of the TWINKLE linker region in progressive external ophthalmoplegia. J Mol Biol. 2008 Mar 28;377(3):691-705. doi: 10.1016/j.jmb.2008.01.035. Epub 2008 Jan 26. Citation on PubMed
  • Li T, Faridi R, Newman WG, Friedman TB. Perrault Syndrome Overview. 2014 Sep 25 [updated 2025 May 8]. In: Adam MP, Bick S, Mirzaa GM, Wallace SE, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from http://www.ncbi.nlm.nih.gov/books/NBK242617/ Citation on PubMed
  • Longley MJ, Humble MM, Sharief FS, Copeland WC. Disease variants of the human mitochondrial DNA helicase encoded by C10orf2 differentially alter protein stability, nucleotide hydrolysis, and helicase activity. J Biol Chem. 2010 Sep 24;285(39):29690-702. doi: 10.1074/jbc.M110.151795. Epub 2010 Jul 20. Citation on PubMed or Free article on PubMed Central
  • Lonnqvist T, Paetau A, Valanne L, Pihko H. Recessive twinkle mutations cause severe epileptic encephalopathy. Brain. 2009 Jun;132(Pt 6):1553-62. doi: 10.1093/brain/awp045. Epub 2009 Mar 20. Citation on PubMed
  • Lopriore P, Unluturk Z, Klopstock T, Karaa A, Rouzier C, Dominguez-Gonzalez C, Lamperti C, Mancuso M; Twinkle-Related Disorders International Consortium for Trial Readiness (TReDIC); Cecchi G, Montano V, Siciliano G, Nicoletta V, Maioli M, Primiano G, Servidei S, La Morgia C, Carelli V, Valentino ML, Caporali L, Arena IG, Musumeci O, Lopergolo D, Malandrini A, Gallus GN, Filosto M, Bello L, Pegoraro E, Comi GP, Magri F, Ronchi D, Di Fonzo A, Percetti M, Azzimonti M, Buchner B, Prokisch H, Bermejo-Guerrero L, Procaccio V, Gaignard P, Echaniz-Laguna A, Schiff M, Rotig A, Toutain A, Paquis-Flucklinger V, Morel G, Robin S, Nadaj-Pakleza A, Chanson JB, Chaussenot A, Ait-El-Mkadem Saadi S, Trimouille A, Tranchant C, Salort-Campana E, Bieth E, Sacconi S, Duval F, Restrepo Vera JL, Molnar MJ, Vissing J, Haas R, Larson A, Enns GM, Parikh S, Goldstein A, Hirano M. Clinical and Genotypic Spectrum of Twinkle-Related Disorders: Insights From a Multinational Cohort Study. Neurology. 2026 Feb 10;106(3):e214401. doi: 10.1212/WNL.0000000000214401. Epub 2026 Jan 15. Citation on PubMed
  • Morino H, Pierce SB, Matsuda Y, Walsh T, Ohsawa R, Newby M, Hiraki-Kamon K, Kuramochi M, Lee MK, Klevit RE, Martin A, Maruyama H, King MC, Kawakami H. Mutations in Twinkle primase-helicase cause Perrault syndrome with neurologic features. Neurology. 2014 Nov 25;83(22):2054-61. doi: 10.1212/WNL.0000000000001036. Epub 2014 Oct 29. Citation on PubMed or Free article on PubMed Central
  • Nikali K, Suomalainen A, Saharinen J, Kuokkanen M, Spelbrink JN, Lonnqvist T, Peltonen L. Infantile onset spinocerebellar ataxia is caused by recessive mutations in mitochondrial proteins Twinkle and Twinky. Hum Mol Genet. 2005 Oct 15;14(20):2981-90. doi: 10.1093/hmg/ddi328. Epub 2005 Aug 31. Citation on PubMed
  • Singh A, Johnson LC, Baruch-Torres N, Yin YW, Patel SS. Human mitochondrial helicase Twinkle has RNA binding, annealing, and strand-exchange activities. Nucleic Acids Res. 2026 Jan 14;54(2):gkag008. doi: 10.1093/nar/gkag008. Citation on PubMed
  • Spelbrink JN, Li FY, Tiranti V, Nikali K, Yuan QP, Tariq M, Wanrooij S, Garrido N, Comi G, Morandi L, Santoro L, Toscano A, Fabrizi GM, Somer H, Croxen R, Beeson D, Poulton J, Suomalainen A, Jacobs HT, Zeviani M, Larsson C. Human mitochondrial DNA deletions associated with mutations in the gene encoding Twinkle, a phage T7 gene 4-like protein localized in mitochondria. Nat Genet. 2001 Jul;28(3):223-31. doi: 10.1038/90058. Citation on PubMed

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