The mitochondria is a cellular organelle that helps the cell convert oxygen to ATP, energy for the cell. The Mitochondria is a unique organelle in that it has its own genome, which contains the mitochondrial DNA called mtDNA (Pohjoismaki J. L., Forslund J. M., Goffart S., & Wanrooij S. 2018). The mitochondria generate ATP energy from food through a process called oxidative phosphorylation (OXPHS). Which involves the flow of electrons from NADH or FADH2 to oxygen with protein complexes located in the mitochondrial inner membrane which then pumps the protons out of the mitochondria, ATP is created when the protons flow back into the mitochondria with the help of an enzyme complex (Berg, J. M., 1970). This is the primary source of ATP in eukaryotic cells, it is comprised of five enzymes complexes that help transport electrons to produce the ATP. The mitochondria functions as a network comprised of genes, enzymes, and proteins that all work together (Li, Y., Zhang, R., Liu, S., Donath, A., Peters, R. S., Ware, J., Zhou, X. 2017). It is estimated to contain 1500 proteins that allows the mitochondria to function few of which come from the mitochondria genes. Which means most of these proteins are coded for by nuclear genes, not the mitochondria genes. The TWNK gene in specific is a nuclear gene that encodes for two of the proteins, Twinkle and Twinky (El-Hattab, A. W., Craigen, W. J., & Scaglia, F., 2017). These proteins function as a 5’-3’ DNA helicase, which is required for the disruption of hydrogen bonds allowing for the temporary unwinding and separation of the mtDNA (El-Hattab, A. W., 2017). The genes cytogenetic location in humans is 10q24.31 which means this gene is located on the long arm of chromosome 10 at position 24.31 (TWNK gene, N.D). The TWNK gene is also known as C10orf2, PEO1, T7-like mitochondrial DNA helicase and twinkle, however TWNK is its most common name (TWNK gene, N.D). The proteins the TWNK gene encodes for play a key role in mtDNA replication, the proteins localize to the mitochondria matrix and mitochondrial nucleoids, which means any mutations in the genes will have a big effect on the organism. The mutations of this gene mean that the mtDNA is not replicated correctly, which can lead to deleted, substituted, and addition of nucleoids in the segments the proteins are trying to replicate. This can lead to the cell not being able to produce ATP effectively causing many problems. One of the most known mutations of this gene is the cause of infantile onset spinocerebellar ataxia or IOSCA (WNK twinkle mtDNA helicase [Homo sapiens (human), N.D). IOSCA is a neurodegenerative disease that starts to show in children around one year of age. This disease causes onset of 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 even more neurological development problems (Lönnqvist T., 2009). Basically, this is a disease that up until age one a child develops normally and then the child starts to experience neurological deficits. This is not the only diseases caused by the mutation of TWNK gene, but a mutation in the TWNK gene is rare and because of this a lot is unknown about the diseases it causes.
Discovery- Reham Aljawi
In 2001, Spelbrink et al. were able to identify the gene C10ORF2 and named it Twinkle [1]. The gene encodes for a protein that resembles T7 GP4 when looking for open reading frames, ORFs, in a region that is linked to PEOA3 (609286) on 10q24 [1]. The team predicted the full length of the protein to be 684 amino acids and a molecular mass of 77 kD [1]. Twinkle has an N-terminus mitochondrial targeting sequence. In comparison, another protein, authors refer to as twinky, is encoded by a variant mRNA that and has 582 amino acids with a molecular mass of 66 kD. The variant lacks residues 579 through 684 and has 4 unique amino acids at the terminal side. Authors found that Twinkle was produced at relatively high levels in skeletal muscle and pancreas but expressed at low levels in the heart. The approximate level of Twinkle expression in skeletal muscle was probably not estimated correctly because of the strong cross-reacting alpha-actin mRNA species just below the beta-actin mRNA [1] [2]. The location of the Twinkle gene is found in the mitochondrial nucleoids and appears with a unique localization pattern that is similar to twinkling stars, hence the name. It was noted that Twinkle is overexpressed in cells that has a relatively increased mtDNA helicase activity [1]. It was also discovered that that function of the gene is critical for the organization and maintenance of human mtDNA fidelity [1].
Another team in 2009 diagnosed a 71-year-old woman with Progressive external ophthalmoplegia, PEO [2]. It was found that it was correlated with the mutation of a gene that caused multiple deletions in mtDNA [2]. Other research suggested that only a point mutation can cause the deletions [4]. The same gene encodes for mtDNA helicase, which later was identified as the Twinkle gene. Samples were taken from muscle cells and blood. When conducting a Southern blot analysis, the deletions were absent. However, they were detected on PCR but only in muscle cells. This suggested that the gene is expressed more in muscles, and this mutation must be screened for even when lacking a family history of PEO or showing negative results in a Southern blot analysis [2].
According to HUGO Gene Nomenclature Committee, HGNC, the approved symbol of the gene is TWNK, and the approved name is Twinkle mtDNA helicase. It can also be found by the ID HGNC:1160 [3].
Researchers were able to identify the enzymatic activities of the Twinkle gene in mtDNA metabolism. They discovered that the unwinding is effectively enhanced when a heterologous single strand-binding protein is present or a single-stranded DNA, ssDNA. It was shown that Twinkle protein, a helicase, act as an antagonist of annealing two complementary ssDNAs. In addition, unlike double-stranded DNA, dsDNA, ssDNA competitively inhibits the annealing activity although both DNAs have shown high affinities. These findings suggest that Twinkle act as both unwinding and annealing mitochondrial DNA [4]. Other researchers were also able to discover that Twinkle is a vital requirement for synthesis of nascent H-strand and other strands in the D-loop and completion of mtDNA replication [5].
Function -Daniel Knorp
The TWNK is a protein coding gene found on the long arm of chromosome 10 (10q24.31). It encodes for two proteins, Twinkle and Twinky. Twinkle is made up of 579-684 amino acids, and Twinky is made up of 582 amino acids.(Lonnqvist, Tuula 2009) Though originating on chromosomes the proteins Twinkle and Twinky are both found in the mitochondria, structures responsible for a process called oxidative phosphorylation, which occurs to convert adenisine-5-triphosphate from food through a combination of anabolic and catabolic reactions. (National Library of Medicine 2016). Each mitochondrion contains its own small amount of DNA which is known as mitochondrial deoxyribonucleic acid (mtDNA). The Twinkle protein, however, is involved in the production of mtDNA. The Twinkle protein functions as a mitochondrial DNA helicase, meaning it binds to DNA and temporarily unwinds the double helix of the DNA molecule so that it can replicate the mtDNA (National Library of Medicine 2016).—(Jeruby Marcellus)
In the mitochondria, these proteins function as an adenine nucleotide dependent helicase. This is a necessary function for the overall maintenance of mtDNA throughout the organism’s life. They also function as either a hexameric or heptameric DNA helicase, which unwinds the double stranded DNA in the 5’ to 3’ direction in short segments. This is accomplished by the removal of hydrogen bonds, which connect the base pairs to each other in a DNA molecule. The proteins unwind single stranded mitochondrial DNA binding protein and mtDNA polymerase gamma. (National Center for Biotechnology) This gene’s encoded proteins function similar to the T7 helicase; however, Twinkle and/ or Twinky are capable of both unwinding and recombining DNA making them bifunctional DNA helicases. (Longley et. Al 2010) They also serve as primases, which are able to initiate DNA replication in the mitochondria. Their functions as a helicase include the binding of both single stranded DNA (ssDNA) and double stranded DNA (dsDNA), and catalyzing DNA unwinding. (Korhonen, J.A., Gaspari, M, Faulkenburg, M 2003) DNA unwinding is accomplished by catalyzing the reaction NTP + H2O –> NDP + phosphate. It has different bonding affinities for each of its specific binding sites when binding either the ssDNA or the dsDNA. In order to function properly there is a requirement of both ATP (adenosine 5'-triphosphate) and MG(2+). (Sen et. al 2012) These proteins are localized to the mitochondrial matrix and mitochondrial nucleoids. This gene also catalyzes the reaction ATP + H(2)O –> ADP + phosphate by working as a hydrolase, which is an enzyme that catalyzes a reaction by using water (H2O) to add hydrogens (H+) or hydroxyl ions (OH-) to a given compound.. (Korohonen, J.A., Pham, X.H., Pellegrini, M., Faulkenburg, M. 2004)
Clinical significance- Jeruby Marcellus
As said above, TWINKLE has been shown to unwind during the DNA replication process and many disease-causing mutations have been mapped to this gene (Milenkovic et al. 2013). According to Gene database, one of those disease-causing mutations are autosomal dominant progressive, external ophthalmoplegia with mitochondrial DNA deletions 3 suggesting that the TWNK gene is pathogenic. Also, according to the Gene Database, this disorder is characterized by the weakness of ocular muscles of the upper eyelid. Patients who have this TWNK gene have other clinical features such has muscle weakness, peripheral neuropathy, cataracts, and depression. It also appears commonly in adults between the ages 18 and 40 slowly worsening over time (“Autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions 3”). The very first sign of progressive external ophthalmoplegia is the drooping of eyelids, ptosis, which can affect either one, or both eyelids. Some affected individuals use their forehead muscles to try and lift the eyelids or lift their chin in order to see clearly if worsens. If the ophthalmoloplegia worsens, which is the weakness of the muscles that move the eye, those that are affected have to turn their head to see in directions (“Autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions 3”). Other symptoms include weakness in muscles contained in the mitochondria, hearing loss, and loss of sensation in the limbs due to nerve damage (“Autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions 3”).
Many Neurologists from the H. Houston Merritt Clinical Research Center for Muscular Dystrophy made a report together that multiple mtDNA features in autosomal dominant and recessive diseases suggest distinct pathogeneses (Carrozzo R. et al 1998). They figured out these multiple mitochondrial DNA deletions have a high amount in autosomal dominant than autosomal recessive disease. By figuring this out, they studied three patients, one with autosomal dominant progressive external ophthalmoplegia, and two with autosomal recessive disorders such as mitochondrial neurogastrointestinal encephalomyopathy and autosomal recessive cardiomyopathy ophthalmoplegia (Carrozzo R. et al 1998). The neurologist used Histochemistry and Southern blot analyses of DNA to determine the skeletal muscle from the patients. The muscle mtDNA was used to characterize the pattern and the amounts of the multiple mtDNA rearrangement; the PCR, polymerase chain reaction, was also performed to obtain the finer maps of the deleted regions in both conditions (Carrozzo R. et al 1998). After the testing, the patients with autosomal dominant progressive external ophthalmoplegia had myopathic features, meaning they showed signs or muscle weakness and the patients with autosomal recessive had multisystem disorders (Carrozzo R. et al 1998). They noticed that the percentage of ragged-red and cytochrome c oxidase-negative fibers were higher in the muscle from the patients with autosomal dominant than the muscles from the patients with autosomal recessive. It is researched that the patients with autosomal dominance had a greater proportion of deleted mtDNA molecules than patients with autosomal recessive. They identified that the patients with autosomal dominant deletion included the mtDNA heavy strand promoter while the patients with autosomal recessive showed no signs of it. This scientific report shows that those with autosomal dominant progressive external ophthalmoplegia are more likely to have proportions of multiple mtDNA deletions in muscle samples than patients with autosomal recessive progressive external ophthalmoplegia (Carrozzo R. et al 1998).
Clinical significance: Mona Kanakrieh
Mutations occur in many different genes and the TWNK gene is one of the genes that has been mutated. Perrault syndrome (PRLTS) causes hearing loss and ovarian dysfunction, which has been discovered in the TWNK gene mutation, that causes the autosomal recessive disorder, and has been found in some patients. The TWNK mutations occurred in an examined sibling with a clinical picture, and a neurological type of PRLTS. Auditory nerve function and cochlear hair cell were used for an examination. To identify the genetic cause disorder an exome sequence was used. A 3D protein was used to tell if there’s any bad effect on the protein function. The results showed two odd mutations in TWNK. Two mutations occurred in the patient’s genes. First mutation was c. 1196A>G(p.ASN399Ser), the second mutation was c. 1802G<A (p.Arg601Gin). The studies of neuroimaging showed that in both patients there was an enlargement in the spinal cord in PRLTS for the first time. They also discovered changes in the nerves and an increase in grey and a decrease in white matter volumes of the cerebellum. The changes that were shown in nerves and dysfunction in cochlear was due to their hearing disorder. In conclusion, PRLTS phenotypic features showed that TWNK gene a part of pathogenesis.
TWNK mutation also occurred in a 6-year-old child with a severe neurological deterioration at the beginning of valproate treatment. WARS2 deficiency was discovered in the child with language disability. She later was treated with sodium valproate after she had a seizure. Her clinical condition got worse and was non-progressive which led to an acute liver failure. Her sodium valproate wasn’t working well so it got stopped and she died after half a year. WARS2 deficiency was also found in two siblings that had slow development which effected their speech and language disability. Another two siblings that had the same deficiency also showed slow development and seizures at a young age. In general, mutations occurred in hepatopathy were related to the sodium valproate treatment.
Another example on the WARS2 deficiency was a male, whose 24 years old. This man died at the age of 24 due to this deficiency. He has developed amyotrophy, spastic quadriplegia, axial hypotonia, dysmetria, tremor and bilateral horizontal nystagmus by the age of 24. This led to his death. Many other examples have suffered from this deficiency. Each of these cases has three different clinical phenotypes that can be distinguished from one another. The three different phenotypes were: a severe neonatal phenotype with overwhelming hyperlacticaemia and fatal outcome at very young age, a more protracted course with early onset developmental delay, motor weakness, extra-pyramidal signs, with or without epilepsy, and a phenotype characterized by normal early development and Parkinson-like symptoms starting around the age of one year. Valproate treatment showed that WARS2 deficiency can be one of the mitochondria defects related with valproate hepatopathy. Pathogenic mutations in WARS2, TWNK and in mitochondrion genes showed that translation and transcription are being affected and related with valproate acute liver failure.
Disease Association Katy Salazar
Mutations occurring on the TWNK gene are associated with health conditions such as Perrault Syndrome, infantile-onset spinocerebellar ataxia, and most prominently progressive external ophthalmoplegia(Oldak et al, 2017). Mutations which occurs on the TWNK gene are classified as missense mutations(Oldak et al, 2017) . Mutations on the TWNK gene lead to decreased mtDNA synthesis which ultimately leads to the reduction and removal of mitochondrial DNA (Rusecka et al, 2018), (Tiller, 2001)
Perrault Syndrome is a rare condition which occurs as a result of compound heterozygous mutations and occurs with an autosomal recessive inheritance pattern meaning individuals with the condition have mutations on both copies of the gene. The condition manifests differently in males and females with the exception of sensorineural hearing loss which affects both sexes. Females exhibit significant reproductive abnormalities and can present with symptoms including abnormal ovary development or a lack of ovaries, amenorrhea or a delayed start in menstruation, and premature ovarian insufficiency in which function is lost (Perrault syndrome-Genetics Home Reference, 2018). In addition many females with the condition experience infertility. Neurological issues such as difficult in learning and delays in normal development, ataxia, and neuropathy(Perrault syndrome 5 – Conditions – GTR – NCBI., n.d.) present in some patients diagnosed with the condition. Genetic testing used to diagnose Perrault Syndrome include sequence analysis of the entire coding region, targeted variant analysis, and deletion/duplication analysis( Perrault syndrome 5 – Conditions – GTR – NCBI., n.d.). (Newman, 2018), (Oldak et al, 2017),(Perrault syndrome-Genetics Home Reference, 2018)
Progressive External Opthalmoplegia (chronic progressive external opthalmoplegia, CPEO, PEO) is a condition of unknown prevalence which can be attributed to heterozygous mutations on the TWNK gene and can either develop as an isolated mutation or through autosomal dominance inheritance(Chronic progressive external ophthalmoplegia, 2017). Individuals affected by the condition commonly experience ptosis, which is the result of weakening muscle function in the muscles which control eye movement and can occur either unilaterally, affecting just one eye, or bilaterally in which both eyes are affected. PEO can also result in the paralysis of the eye muscles called opthalmoplegia. Additionally, individuals with the condition have the potential to experience myopathy which can occur in the “neck, arms, or legs.”(Progressive external ophthalmoplegia – Conditions – GTR – NCBI, n.d.) and dysphagia or difficulty in swallowing. Common genetic tests which can be used to diagnose Progressive External Opthalmoplegia include deletion/duplication analysis, sequence analysis of select exons, mutation scanning of the entire coding region, sequence analysis of the entire coding region, targeted variant analysis, and mutation scanning of select exons (Progressive external ophthalmoplegia – Conditions – GTR – NCBI, n.d.). (Autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions 3, n.d.), (Chronic progressive external ophthalmoplegia, 2017), (Progressive external ophthalmoplegia – Conditions – GTR – NCBI, n.d.), (Progressive external opthalmoplegia-Genetics Home Reference, 2018).
Infantile-Onset Spinocerebellar Ataxia (Mitochondrial DNA Depletion Syndrome 7: hepatoerebral type)(Kniffin, 1994) is a neurodegenerative disease which takes on an autosomal recessive pattern of inheritance when associated with a mutation on the TWNK gene and presents in affected individuals around one year of age. Clinical features of the disease include “spinocerebellar ataxia, muscle hypotonia, athetoid movements, loss of deep-tendon reflexes, hearing deficit, opthalmoplegia, optic atrophy, primary hypergonadotropic hypogonadism in females, and epileptic encephalopathy.”( Lönnqvist, 2018) Common genetic testing used in diagnosing Infantile-Onset Spinocerebellar Ataxia include sequence analysis of the entire coding region, targeted variant analysis, and deletion/duplication analysis. (Kniffin, 1994), (Mitochondrial DNA depletion syndrome 7(hepatocerebral type), n.d)
(Katy Salazar)
References
“TWNK Gene – Genetics Home Reference – NIH.” U.S. National Library of Medicine,
National Institutes of Health, May 2016, ghr.nlm.nih.gov/gene/TWNK.
Carrozzo, R. et al.Multiple mtDNA deletions features in autosomal dominant and recessive
diseases suggest distinct pathogeneses. Current neurology and neuroscience reports.(1998). Available at: https://www.ncbi.nlm.nih.gov/pubmed/9443465. (Accessed: 10th November 2018)
Autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions 3
(Concept Id: C1836439) – MedGen – NCBI. Current neurology and neurosciencereports. Available at: https://www.ncbi.nlm.nih.gov/medgen/C1836439. (Accessed: 9th November 2018)
Milenkovic, D. et al.TWINKLE is an essential mitochondrial helicase required for synthesis of
nascent D-loop strands and complete mtDNA replication. Current neurology and neuroscience reports.(2013). Available at: https://www.ncbi.nlm.nih.gov/pubmed/23393161. (Accessed: 9th November 2018)
Gene Database. TWNK Gene(Protein Coding). ESPL1 Gene – GeneCards | ESPL1 Protein |ESPL1
AntibodyAvailable at: https://www.genecards.org/cgi-bin/carddisp.pl?gene=TWNK#publications. (Accessed: 9th November 2018)
El-Hattab, A. W., Craigen, W. J., & Scaglia, F. (n.d.). Mitochondrial DNA maintenance defects. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE, 1863(6), 1539–1555. https://doi.org/10.1016/j.bbadis.2017.02.017
Berg, J. M. (1970, January 01). Oxidative Phosphorylation. Retrieved from https://www.ncbi.nlm.nih.gov/books/NBK21208/
TWNK gene – Genetics Home Reference – NIH. (n.d.). Retrieved from https://ghr.nlm.nih.gov/gene/TWNK#resources
TWNK twinkle mtDNA helicase [Homo sapiens (human)] – Gene – NCBI. (n.d.). Retrieved from https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=DetailsSearch&Term=56652
Lönnqvist T. Infantile-Onset Spinocerebellar Ataxia. 2009 Jan 27 [Updated 2018 Apr 19]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018.
Vantroys, Elise, et al. “Severe Hepatopathy and Neurological Deterioration after Start of Valproate Treatment in a 6-Year-Old Child with Mitochondrial Tryptophanyl-TRNA Synthetase Deficiency.” Orphanet Journal of Rare Diseases, vol. 13, no. 1, May 2018, p. N.PAG. EBSCOhost, doi:10.1186/s13023-018-0822-6.
Ołdak, Monika, et al. “Novel Neuro-Audiological Findings and Further Evidence for TWNK Involvement in Perrault Syndrome.” Journal of Translational Medicine, vol. 15, Feb. 2017, pp. 1–13. EBSCOhost, doi:10.1186/s12967-017-1129-4.
[1] Spelbrink, J. N., Li, F.-Y., Tiranti, V., Nikali, K., Yuan, Q.-P., Tariq, M., Wanrooij, S., Garrido, N., Comi, G., Morandi, L., Santoro, L., Toscano, A., and 9 others. “Human mitochondrial DNA deletions associated with mutations in the gene encoding twinkle, a phage T7 gene 4-like protein localized in mitochondria”. Nature Genet. 28: 223-231, 2001. Note: Erratum: Nature Genet. 29: 100 only, 2001.
[2] Van Hove, J. L. K., Cunningham, V., Rice, C., Ringel, S. P., Zhang, Q., Chou, P.-C., Truong, C. K., Wong, L.-J. C. “Finding twinkle in the eyes of a 71-year-old lady: A case report and review of the genotypic and phenotypic spectrum of TWINKLE-related dominant disease”. Am. J. Med. Genet. 149A: 861-867, 2009.
[3] Milenkovic, D., Matic, S., Kühl, I., Ruzzenente, B., Freyer, C., Jemt, E., Park, C. B., Falkenberg, M., … Larsson, N. G. (2013). “TWINKLE is an essential mitochondrial helicase required for synthesis of nascent D-loop strands and complete mtDNA replication”. Human molecular genetics, 22(10), 1983-93. PMID: 23393161.
[4] Symbol Report: TWNK. (n.d.). Retrieved from https://www.genenames.org/cgi-bin/gene_symbol_report?hgnc_id=HGNC:1160.
[5] Sen, D., Nandakumar, D., Tang, G. Q., & Patel, S. S. (2012). “Human mitochondrial DNA helicase TWINKLE is both an unwinding and annealing helicase”. The Journal of biological chemistry, 287(18), 14545-56. PMID: 22383523.
Autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions 3 – Conditions – GTR – NCBI. (n.d.). Retrieved November 10, 2018, from https://www.ncbi.nlm.nih.gov/gtr/conditions/C1836439/
Chronic progressive external ophthalmoplegia. (2017, January 19). Retrieved November 09, 2018, from https://rarediseases.info.nih.gov/diseases/4503/chronic-progressive-external-ophthalmoplegia
Kniffin, C. L. (1994, April 01). 271245-MITOCHONDRIAL DNA DEPLETION SYNDROME 7 (HEPATOCEREBRAL TYPE); MTDPS7. Retrieved November 10, 2018, from https://www.omim.org/entry/271245
Lönnqvist, T. (2018, April 19). Infantile-Onset Spinocerebellar Ataxia. Retrieved November 10, 2018, from https://www.ncbi.nlm.nih.gov/books/NBK3795/
Mitochondrial DNA depletion syndrome 7 (hepatocerebral type) – Conditions – GTR – NCBI. (n.d.). Retrieved November 10, 2018, from https://www.ncbi.nlm.nih.gov/gtr/conditions/C1849096/
Newman, W. G. (2018, September 06). Perrault Syndrome. Retrieved November 10, 2018, from https://www.ncbi.nlm.nih.gov/books/NBK242617/#perrault.Summary
Ołdak, M., Oziębło, D., Pollak, A., Stępniak, I., Lazniewski, M., Lechowicz, U., . . . Skarżyński, H. (2017, February 08). Novel neuro-audiological findings and further evidence for TWNK involvement in Perrault syndrome. Retrieved November 10, 2018, from https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-017-1129-4
Perrault syndrome – Genetics Home Reference – NIH. (2018, November 07). Retrieved November 10, 2018, from https://ghr.nlm.nih.gov/condition/perrault-syndrome
Perrault syndrome 5 – Conditions – GTR – NCBI. (n.d.). Retrieved November 10, 2018, from https://www.ncbi.nlm.nih.gov/gtr/conditions/C4015307/
Progressive external ophthalmoplegia – Conditions – GTR – NCBI. (n.d.). Retrieved November 10, 2018, from https://www.ncbi.nlm.nih.gov/gtr/conditions/C0162674/
Progressive external ophthalmoplegia – Genetics Home Reference – NIH. (2018, November 07). Retrieved November 10, 2018, from https://ghr.nlm.nih.gov/condition/progressive-external-ophthalmoplegia#genes
Rusecka, J., Kaliszewska, M., Bartnik, E., & Tońska, K. (2018, January 17). Nuclear genes involved in mitochondrial diseases caused by instability of mitochondrial DNA. Retrieved November 10, 2018, from https://link.springer.com/article/10.1007/s13353-017-0424-3
Tiller, G. E. (2001, June 28). 60675-TWINKLE mtDNA HELICASE; TWNK. Retrieved November 10, 2018, from https://www.omim.org/entry/606075