Twinkle (protein)

Last updated
TWNK
Identifiers
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
Orthologs
SpeciesHumanMouse
Entrez

56652

226153

Ensembl

ENSG00000107815

ENSMUSG00000025209

UniProt

Q96RR1

Q8CIW5

RefSeq (mRNA)

NM_001163812
NM_001163813
NM_001163814
NM_021830
NM_001368275

Contents

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 Mb Chr 19: 44.99 – 45 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/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

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

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

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

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]

Related Research Articles

<span class="mw-page-title-main">Helicase</span> Class of enzymes to unpack an organisms genes

Helicases are a class of enzymes thought to be vital to all organisms. Their main function is to unpack an organism's genetic material. Helicases are motor proteins that move directionally along a nucleic acid phosphodiester backbone, separating two hybridized nucleic acid strands, using energy from ATP hydrolysis. There are many helicases, representing the great variety of processes in which strand separation must be catalyzed. Approximately 1% of eukaryotic genes code for helicases.

<span class="mw-page-title-main">Spinocerebellar ataxia</span> Medical condition

Spinocerebellar ataxia (SCA) is a progressive, degenerative, genetic disease with multiple types, each of which could be considered a neurological condition in its own right. An estimated 150,000 people in the United States have a diagnosis of spinocerebellar ataxia at any given time. SCA is hereditary, progressive, degenerative, and often fatal. There is no known effective treatment or cure. SCA can affect anyone of any age. The disease is caused by either a recessive or dominant gene. In many cases people are not aware that they carry a relevant gene until they have children who begin to show signs of having the disorder.

Kearns–Sayre syndrome (KSS), oculocraniosomatic disorder or oculocranionsomatic neuromuscular disorder with ragged red fibers is a mitochondrial myopathy with a typical onset before 20 years of age. KSS is a more severe syndromic variant of chronic progressive external ophthalmoplegia, a syndrome that is characterized by isolated involvement of the muscles controlling movement of the eyelid and eye. This results in ptosis and ophthalmoplegia respectively. KSS involves a combination of the already described CPEO as well as pigmentary retinopathy in both eyes and cardiac conduction abnormalities. Other symptoms may include cerebellar ataxia, proximal muscle weakness, deafness, diabetes mellitus, growth hormone deficiency, hypoparathyroidism, and other endocrinopathies. In both of these diseases, muscle involvement may begin unilaterally but always develops into a bilateral deficit, and the course is progressive. This discussion is limited specifically to the more severe and systemically involved variant.

T7 DNA helicase (gp4) is a hexameric motor protein encoded by T7 phages that uses energy from dTTP hydrolysis to process unidirectionally along single stranded DNA, separating (helicase) the two strands as it progresses. It is also a primase, making short stretches of RNA that initiates DNA synthesis. It forms a complex with T7 DNA polymerase. Its homologs are found in mitochondria and chloroplasts.

<span class="mw-page-title-main">MERRF syndrome</span> Medical condition

MERRF syndrome is a mitochondrial disease. It is extremely rare, and has varying degrees of expressivity owing to heteroplasmy. MERRF syndrome affects different parts of the body, particularly the muscles and nervous system. The signs and symptoms of this disorder appear at an early age, generally childhood or adolescence. The causes of MERRF syndrome are difficult to determine, but because it is a mitochondrial disorder, it can be caused by the mutation of nuclear DNA or mitochondrial DNA. The classification of this disease varies from patient to patient, since many individuals do not fall into one specific disease category. The primary features displayed on a person with MERRF include myoclonus, seizures, cerebellar ataxia, myopathy, and ragged red fibers (RRF) on muscle biopsy, leading to the disease's name. Secondary features include dementia, optic atrophy, bilateral deafness, peripheral neuropathy, spasticity, or multiple lipomata. Mitochondrial disorders, including MERRFS, may present at any age.

Chronic progressive external ophthalmoplegia (CPEO) is a type of eye disorder characterized by slowly progressive inability to move the eyes and eyebrows. It is often the only feature of mitochondrial disease, in which case the term CPEO may be given as the diagnosis. In other people suffering from mitochondrial disease, CPEO occurs as part of a syndrome involving more than one part of the body, such as Kearns–Sayre syndrome. Occasionally CPEO may be caused by conditions other than mitochondrial diseases.

<span class="mw-page-title-main">MT-ATP8</span> Mitochondrial protein-coding gene whose product is involved in ATP synthesis

MT-ATP8 is a mitochondrial gene with the full name 'mitochondrially encoded ATP synthase membrane subunit 8' that encodes a subunit of mitochondrial ATP synthase, ATP synthase Fo subunit 8. This subunit belongs to the Fo complex of the large, transmembrane F-type ATP synthase. This enzyme, which is also known as complex V, is responsible for the final step of oxidative phosphorylation in the electron transport chain. Specifically, one segment of ATP synthase allows positively charged ions, called protons, to flow across a specialized membrane inside mitochondria. Another segment of the enzyme uses the energy created by this proton flow to convert a molecule called adenosine diphosphate (ADP) to ATP. Subunit 8 differs in sequence between Metazoa, plants and Fungi.

<span class="mw-page-title-main">MT-ATP6</span> Mitochondrial protein-coding gene whose product is involved in ATP synthesis

MT-ATP6 is a mitochondrial gene with the full name 'mitochondrially encoded ATP synthase membrane subunit 6' that encodes the ATP synthase Fo subunit 6. This subunit belongs to the Fo complex of the large, transmembrane F-type ATP synthase. This enzyme, which is also known as complex V, is responsible for the final step of oxidative phosphorylation in the electron transport chain. Specifically, one segment of ATP synthase allows positively charged ions, called protons, to flow across a specialized membrane inside mitochondria. Another segment of the enzyme uses the energy created by this proton flow to convert a molecule called adenosine diphosphate (ADP) to ATP. Mutations in the MT-ATP6 gene have been found in approximately 10 to 20 percent of people with Leigh syndrome.

Mitochondrially encoded tRNA histidine, also known as MT-TH, is a transfer RNA which, in humans, is encoded by the mitochondrial MT-TH gene.

<span class="mw-page-title-main">POLG</span> Protein-coding gene in the species Homo sapiens

DNA polymerase subunit gamma is an enzyme that in humans is encoded by the POLG gene. Mitochondrial DNA polymerase is heterotrimeric, consisting of a homodimer of accessory subunits plus a catalytic subunit. The protein encoded by this gene is the catalytic subunit of mitochondrial DNA polymerase. Defects in this gene are a cause of progressive external ophthalmoplegia with mitochondrial DNA deletions 1 (PEOA1), sensory ataxic neuropathy dysarthria and ophthalmoparesis (SANDO), Alpers-Huttenlocher syndrome (AHS), and mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE).

<span class="mw-page-title-main">TFAM</span> Protein-coding gene in the species Homo sapiens

Mitochondrial transcription factor A, abbreviated as TFAM or mtTFA, is a protein that in humans is encoded by the TFAM gene.

<span class="mw-page-title-main">SETX</span> Protein-coding gene in the species Homo sapiens

Probable helicase senataxin is an enzyme that in humans is encoded by the SETX gene.

<span class="mw-page-title-main">Ataxin 10</span> Protein-coding gene in the species Homo sapiens

Ataxin-10 is a protein that in humans is encoded by the ATXN10 gene.

Ataxin 8 opposite strand, also known as ATXN8OS, is a human gene.

Mitochondrially encoded tRNA valine also known as MT-TV is a transfer RNA which in humans is encoded by the mitochondrial MT-TV gene.

Mitochondrially encoded tRNA glutamic acid also known as MT-TE is a transfer RNA which in humans is encoded by the mitochondrial MT-TE gene. MT-TE is a small 69 nucleotide RNA that transfers the amino acid glutamic acid to a growing polypeptide chain at the ribosome site of protein synthesis during translation.

Mitochondrially encoded tRNA isoleucine also known as MT-TI is a transfer RNA which in humans is encoded by the mitochondrial MT-TI gene.

Mitochondrially encoded tRNA asparagine also known as MT-TN is a transfer RNA which in humans is encoded by the mitochondrial MT-TN gene.

Mitochondrially encoded tRNA tyrosine, also known as MT-TY, is a transfer RNA which in humans is encoded by the mitochondrial MT-TY gene.

<span class="mw-page-title-main">Mitochondrial DNA depletion syndrome</span> Medical condition

Mitochondrial DNA depletion syndrome, or Alper's disease, is any of a group of autosomal recessive disorders that cause a significant drop in mitochondrial DNA in affected tissues. Symptoms can be any combination of myopathic, hepatopathic, or encephalomyopathic. These syndromes affect tissue in the muscle, liver, or both the muscle and brain, respectively. The condition is typically fatal in infancy and early childhood, though some have survived to their teenage years with the myopathic variant and some have survived into adulthood with the SUCLA2 encephalomyopathic variant. There is currently no curative treatment for any form of MDDS, though some preliminary treatments have shown a reduction in symptoms.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000107815 - Ensembl, May 2017
  2. 1 2 3 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. 1 2 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 31 January 2024). PMID   10645945.{{cite journal}}: CS1 maint: DOI inactive as of January 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. 1 2 "Entrez Gene: PEO1 progressive external ophthalmoplegia 1".
  9. 1 2 3 4 "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. 1 2 3 Online Mendelian Inheritance in Man (OMIM): TWINKLE mtDNA HELICASE; TWNK - 606075
  12. ↑ "TWNK twinkle mtDNA helicase [Homo sapiens (human)] - Gene". NCBI.
  13. 1 2 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.

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