User:Mona Kanakrieh/Twinkle(protein)

General Information
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 together (Li, Y., Zhang, R., Liu, S., Donath, A., Peters, R. S., Ware, J., Zhou, X. 2017).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. et al., 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. et al., 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 (TWNK 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. Clinical significance: 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 child, whose age is 6, 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 as well as a deadly sign, at a young age. There are several symptoms of the disease that can be caught at an early stage of life. Such as, the delay of the development of the body, and a motor disadvantage. 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.

References:

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.

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.

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/

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.

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

TWNK gene - Genetics Home Reference - NIH. (n.d.). Retrieved from https://ghr.nlm.nih.gov/gene/TWNK#resources

Li, Y., Zhang, R., Liu, S., Donath, A., Peters, R. S., Ware, J., … Zhou, X. (2017). The molecular evolutionary dynamics of oxidative phosphorylation (OXPHOS) genes in Hymenoptera. BMC Evolutionary Biology, (1). https://doi.org/10.1186/s12862-017-1111-z