Twinkle (protein)
TWNK | |||||||||||||||||||||||||||||||||||||||||||||||||||
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Aliases | TWNK, ATXN8, IOSCA, MTDPS7, PEO, PEO1, PEOA3, SANDO, SCA8, TWINL, PRLTS5, C10orf2, chromosome 10 open reading frame 2, twinkle mtDNA helicase | ||||||||||||||||||||||||||||||||||||||||||||||||||
External IDs | OMIM: 606075; MGI: 2137410; HomoloGene: 11052; GeneCards: TWNK; OMA:TWNK - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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Twinkle protein also known as twinkle mtDNA helicase is a mitochondrial protein that in humans is encoded by the TWNK gene (also known as C10orf2 or PEO1) located in the long arm of chromosome 10 (10q24.31).[5][6][7][8][9]
Twinkle is a mitochondrial protein with structural similarity to the phage T7 primase/helicase (GP4) and other hexameric ring helicases. The twinkle protein colocalizes with mtDNA in mitochondrial nucleoids, and its name derives from the unusual localization pattern reminiscent of twinkling stars.[5][8] A homolog (B5X582) is found in Arabidopsis thaliana chloroplast and mitochondria.[10]
Discovery
[edit]In 2001, a team was able to identify the C10orf2 gene and named it twinkle due to its localization pattern that resembles twinkling stars.[11] The presumed main function of twinkle is important for the lifetime regulation of the human mtDNA. The gene is expressed at high levels in skeletal muscles.[11] The gene encodes for a protein that has a full-length of 684 units of amino acids. The twinkle protein consists of 3 functional domains: a 5-primase domain, a linker region, and a helicase region. The linker and helicase regions are involved in most of the pathogenic mutations.[11]
Function
[edit]The TWNK gene makes two proteins, Twinkle and Twinky. The proteins Twinkle and Twinky are both found in the mitochondria.[9] Each mitochondrion contains a small amount of DNA which is known as mitochondrial DNA (mtDNA). The Twinkle protein is involved in the production of mtDNA by functioning as an adenine nucleotide dependent DNA helicase, an enzyme that binds to DNA and temporarily unwinds the double helix of the DNA molecule so that it can replicate.[9] They also serve as primases able to initiate DNA replication.
They function as hexameric or heptameric DNA helicases, which unwinds the double-stranded DNA in the 5’ to 3’ direction in short segments. The proteins unwind single-stranded mitochondrial DNA binding protein and mtDNA polymerase gamma. These enzymes function similar to the T7 phage helicase (gp4); however, Twinkle and/ or Twinky are capable of both unwinding and recombining DNA making them bifunctional helicases.
Their functions as a helicase include the binding of both single stranded DNA (ssDNA) and double stranded DNA (dsDNA), and catalyzing DNA unwinding. The energy required for DNA unwinding is supplied by the hydrolysis of ATP to ADP. It has different binding affinities for each of its specific binding sites when binding either the ssDNA or the dsDNA.
Disease association
[edit]Mutations occurring on the TWNK gene are associated with health conditions such as Perrault Syndrome, ataxia neuropathy spectrum, infantile-onset spinocerebellar ataxia, and most prominently progressive external ophthalmoplegia.[9]
One of the best known mutations of this gene is associated with infantile onset spinocerebellar ataxia or IOSCA.[12] IOSCA is a neurodegenerative disease whose symptoms appear in children after one year of age. The symptoms of this disease include ataxia, muscle hypertonia, loss of deep-tendon reflexes, and athetosis and later on in the child's life hearing loss, psychotic behavior, sensory axonal neutrophil ataxia, and additional neurological development problems.[13] Before age one, a child develops normally and then the child starts to experience neurological deficits.[13]
Clinical significance
[edit]The twinkle gene is an important protein that is involved in the synthesis and maintenance of mtDNA. The gene is located in the mitochondrial matrix and mitochondrial nucleotides. Twinkle protein serves as the mitochondrial DNA helicase that binds to DNA and aids in unwinding the double helix of the DNA molecules. By allowing unwinding of the double helix, replication of mtDNA is achieved. Any form of mutation in twinkle protein can result in mtDNA disease. The disease can be categorized into two groups. The first category includes disease that impairs the respiratory function due to the primary mutation of the mtDNA; the second category is usually known as mtDNA maintenance disease. The cause of mtDNA maintenance diseases is the dysfunction of the replication and maintenance apparatus of mtDNA, programmed by nuclear genes. Infantile onset spinocerebellar ataxia (IOSCA) and progressive external ophthalmoplegia (PEO) are associated with multiple deletions of mtDNA. PEO in humans and most mammals is associated with an eye disorder which involves the individual gradually losing the ability to move the eyes as well as the eyebrows. These disorders in recent times have been established to be occurring in the population, with the frequencies of single mutation projected to increase.
Transgenic mice expressing both human PEO patient mutations and the wild-type mouse twinkle protein have progressive respiratory chain dysfunction due to accumulation of mtDNA deletions, but the phenotype does not reduce lifespan.[14]
References
[edit]- ^ a b c GRCh38: Ensembl release 89: ENSG00000107815 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000025209 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ a b Spelbrink JN, Li FY, Tiranti V, Nikali K, Yuan QP, Tariq M, et al. (July 2001). "Human mitochondrial DNA deletions associated with mutations in the gene encoding Twinkle, a phage T7 gene 4-like protein localized in mitochondria". Nature Genetics. 28 (3): 223–31. doi:10.1038/90058. PMID 11431692. S2CID 22237030.
- ^ Leipe DD, Aravind L, Grishin NV, Koonin EV (January 2000). "The bacterial replicative helicase DnaB evolved from a RecA duplication". Genome Research. 10 (1): 5–16. doi:10.1101/gr.10.1.5 (inactive 31 January 2024). PMID 10648635.
{{cite journal}}
: CS1 maint: DOI inactive as of January 2024 (link) - ^ Nikali K, Suomalainen A, Saharinen J, Kuokkanen M, Spelbrink JN, Lönnqvist T, Peltonen L (October 2005). "Infantile onset spinocerebellar ataxia is caused by recessive mutations in mitochondrial proteins Twinkle and Twinky". Human Molecular Genetics. 14 (20): 2981–90. doi:10.1093/hmg/ddi328. PMID 16135556.
- ^ a b "Entrez Gene: PEO1 progressive external ophthalmoplegia 1".
- ^ a b c d "TWNK gene". Genetics Home Reference.
- ^ Diray-Arce, J; Liu, B; Cupp, JD; Hunt, T; Nielsen, BL (4 March 2013). "The Arabidopsis At1g30680 gene encodes a homologue to the phage T7 gp4 protein that has both DNA primase and DNA helicase activities". BMC Plant Biology. 13: 36. doi:10.1186/1471-2229-13-36. PMC 3610141. PMID 23452619.
- ^ a b c Online Mendelian Inheritance in Man (OMIM): TWINKLE mtDNA HELICASE; TWNK - 606075
- ^ "TWNK twinkle mtDNA helicase [Homo sapiens (human)] - Gene". NCBI.
- ^ a b Lönnqvist T (2016). "Infantile-Onset Spinocerebellar Ataxia (IOSCA)". In Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJ, Stephens K, Amemiya A (eds.). GeneReviews. University of Washington, Seattle. pp. 171–178. PMID 20301746.
- ^ Tyynismaa H, Mjosund KP, Wanrooij S, Lappalainen I, Ylikallio E, Jalanko A, Spelbrink JN, Paetau A, Suomalainen A (2005). "Mutant mitochondrial helicase Twinkle causes multiple mtDNA deletions and a late-onset mitochondrial disease in mice". Proc Natl Acad Sci U S A. 102 (49): 17687–92. Bibcode:2005PNAS..10217687T. doi:10.1073/pnas.0505551102. PMC 1308896. PMID 16301523.
Further reading
[edit]- Suomalainen A, Kaukonen J, Amati P, Timonen R, Haltia M, Weissenbach J, Zeviani M, Somer H, Peltonen L (February 1995). "An autosomal locus predisposing to deletions of mitochondrial DNA". Nature Genetics. 9 (2): 146–51. doi:10.1038/ng0295-146. PMID 7719341. S2CID 32160642.
- Hirano M, DiMauro S (December 2001). "ANT1, Twinkle, POLG, and TP: new genes open our eyes to ophthalmoplegia". Neurology. 57 (12): 2163–5. doi:10.1212/wnl.57.12.2163. PMID 11756592. S2CID 42784334.
- Lewis S, Hutchison W, Thyagarajan D, Dahl HH (September 2002). "Clinical and molecular features of adPEO due to mutations in the Twinkle gene". Journal of the Neurological Sciences. 201 (1–2): 39–44. doi:10.1016/S0022-510X(02)00190-9. PMID 12163192. S2CID 44270654.
- Arenas J, Briem E, Dahl H, Hutchison W, Lewis S, Martin MA, Spelbrink H, Tiranti V, Jacobs H, Zeviani M (February 2003). "The V368i mutation in Twinkle does not segregate with AdPEO". Annals of Neurology. 53 (2): 278. doi:10.1002/ana.10430. PMID 12557300. S2CID 12656289.
- Garrido N, Griparic L, Jokitalo E, Wartiovaara J, van der Bliek AM, Spelbrink JN (April 2003). "Composition and dynamics of human mitochondrial nucleoids". Molecular Biology of the Cell. 14 (4): 1583–96. doi:10.1091/mbc.E02-07-0399. PMC 153124. PMID 12686611.
- Agostino A, Valletta L, Chinnery PF, Ferrari G, Carrara F, Taylor RW, Schaefer AM, Turnbull DM, Tiranti V, Zeviani M (April 2003). "Mutations of ANT1, Twinkle, and POLG1 in sporadic progressive external ophthalmoplegia (PEO)". Neurology. 60 (8): 1354–6. doi:10.1212/01.wnl.0000056088.09408.3c. PMID 12707443. S2CID 31209510.
- Van Goethem G, Löfgren A, Dermaut B, Ceuterick C, Martin JJ, Van Broeckhoven C (August 2003). "Digenic progressive external ophthalmoplegia in a sporadic patient: recessive mutations in POLG and C10orf2/Twinkle". Human Mutation. 22 (2): 175–6. doi:10.1002/humu.10246. PMID 12872260. S2CID 35604757.
- Deschauer M, Kiefer R, Blakely EL, He L, Zierz S, Turnbull DM, Taylor RW (September 2003). "A novel Twinkle gene mutation in autosomal dominant progressive external ophthalmoplegia". Neuromuscular Disorders. 13 (7–8): 568–72. doi:10.1016/S0960-8966(03)00071-3. PMID 12921794. S2CID 23020569.
- Korhonen JA, Gaspari M, Falkenberg M (December 2003). "TWINKLE Has 5' -> 3' DNA helicase activity and is specifically stimulated by mitochondrial single-stranded DNA-binding protein". The Journal of Biological Chemistry. 278 (49): 48627–32. doi:10.1074/jbc.M306981200. PMID 12975372. S2CID 12598297.
- Korhonen JA, Pham XH, Pellegrini M, Falkenberg M (June 2004). "Reconstitution of a minimal mtDNA replisome in vitro". The EMBO Journal. 23 (12): 2423–9. doi:10.1038/sj.emboj.7600257. PMC 423294. PMID 15167897.
- Wanrooij S, Luoma P, van Goethem G, van Broeckhoven C, Suomalainen A, Spelbrink JN (2004). "Twinkle and POLG defects enhance age-dependent accumulation of mutations in the control region of mtDNA". Nucleic Acids Research. 32 (10): 3053–64. doi:10.1093/nar/gkh634. PMC 434440. PMID 15181170.
- Tyynismaa H, Sembongi H, Bokori-Brown M, Granycome C, Ashley N, Poulton J, Jalanko A, Spelbrink JN, Holt IJ, Suomalainen A (December 2004). "Twinkle helicase is essential for mtDNA maintenance and regulates mtDNA copy number". Human Molecular Genetics. 13 (24): 3219–27. doi:10.1093/hmg/ddh342. PMID 15509589.
- Hudson G, Deschauer M, Busse K, Zierz S, Chinnery PF (January 2005). "Sensory ataxic neuropathy due to a novel C10Orf2 mutation with probable germline mosaicism". Neurology. 64 (2): 371–3. doi:10.1212/01.WNL.0000149767.51152.83. PMID 15668446. S2CID 36540686.
- Ziebarth TD, Farr CL, Kaguni LS (April 2007). "Modular architecture of the hexameric human mitochondrial DNA helicase". Journal of Molecular Biology. 367 (5): 1382–91. doi:10.1016/j.jmb.2007.01.079. PMC 2711006. PMID 17324440.
- Baloh RH, Salavaggione E, Milbrandt J, Pestronk A (July 2007). "Familial parkinsonism and ophthalmoplegia from a mutation in the mitochondrial DNA helicase twinkle". Archives of Neurology. 64 (7): 998–1000. doi:10.1001/archneur.64.7.998. PMID 17620490.
- Sarzi E, Goffart S, Serre V, Chrétien D, Slama A, Munnich A, Spelbrink JN, Rötig A (December 2007). "Twinkle helicase (PEO1) gene mutation causes mitochondrial DNA depletion". Annals of Neurology. 62 (6): 579–87. doi:10.1002/ana.21207. PMID 17722119. S2CID 30878068.
- Ołdak M, Oziębło D, Pollak A, Stępniak I, Lazniewski M, Lechowicz U, Kochanek K, Furmanek M, Tacikowska G, Plewczynski D, Wolak T, Płoski R, Skarżyński H (February 2017). "Novel neuro-audiological findings and further evidence for TWNK involvement in Perrault syndrome". Journal of Translational Medicine. 15 (1): 25. doi:10.1186/s12967-017-1129-4. PMC 5299684. PMID 28178980.