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Twinkle (protein)

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(Redirected from ATXN8)
TWNK
Identifiers
AliasesTWNK, ATXN8, IOSCA, MTDPS7, PEO, PEO1, PEOA3, SANDO, SCA8, TWINL, PRLTS5, C10orf2, chromosome 10 open reading frame 2, twinkle mtDNA helicase
External IDsOMIM: 606075; MGI: 2137410; HomoloGene: 11052; GeneCards: TWNK; OMA:TWNK - orthologs
Orthologs
SpeciesHumanMouse
Entrez

56652

226153

Ensembl

ENSG00000107815

ENSMUSG00000025209

UniProt

Q96RR1

Q8CIW5

RefSeq (mRNA)

NM_001163812
NM_001163813
NM_001163814
NM_021830
NM_001368275

NM_153796
NM_001348254
NM_001348259

RefSeq (protein)

NP_001157284
NP_001157285
NP_001157286
NP_068602
NP_001355204

NP_722491
NP_001335183
NP_001335188

Location (UCSC)Chr 10: 100.99 – 100.99 MbChr 19: 44.99 – 45 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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

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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

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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

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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

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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

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000107815 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000025209 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ 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.
  6. ^ 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 1 November 2024). PMID 10645945.{{cite journal}}: CS1 maint: DOI inactive as of November 2024 (link)
  7. ^ 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.
  8. ^ a b "Entrez Gene: PEO1 progressive external ophthalmoplegia 1".
  9. ^ a b c d "TWNK gene". Genetics Home Reference.
  10. ^ 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.
  11. ^ a b c Online Mendelian Inheritance in Man (OMIM): TWINKLE mtDNA HELICASE; TWNK - 606075
  12. ^ "TWNK twinkle mtDNA helicase [Homo sapiens (human)] - Gene". NCBI.
  13. ^ 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.
  14. ^ 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

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