This report describes PEOA3, a subtype of progressive external ophthalmoplegia with mitochondrial DNA deletions; PEOA3 exhibits autosomal dominant inheritance. The human gene implicated in this disease is TWNK, which encodes mtDNA helicase. There is a single orthologous gene in Drosophila, mtDNA-helicase, for which RNAi-targeting constructs and alleles caused by insertional mutagenesis have been generated. Human TWNK is implicated in multiple diseases (see MIM:606075); the variants characterized in flies are associated with PEOA3.
The human TWNK has not been introduced into flies.
Variant(s) implicated in human disease tested (as analogous mutation in fly gene): A442P in the fly mtDNA-helicase gene (corresponds to A475P in the human TWNK gene); W441C in the fly mtDNA-helicase gene (corresponds to W474C in the human TWNK gene). Overexpression of a transgene with the A442P variant or a transgene with a lesion in the protein active site results in larval or pupal lethality. The mitochondrial impairment caused by these mutations promotes apoptosis.
[updated Apr. 2018 by FlyBase; FBrf0222196]
Progressive external ophthalmoplegia is characterized by multiple mitochondrial DNA deletions in skeletal muscle. The most common clinical features include adult onset of weakness of the external eye muscles and exercise intolerance. Additional symptoms are variable, and may include cataracts, hearing loss, sensory axonal neuropathy, ataxia, depression, hypogonadism, and parkinsonism. Both autosomal dominant and autosomal recessive inheritance can occur; autosomal recessive inheritance is usually more severe (Filosto et al., 2003, pubmed:12975295; Luoma et al., 2004, pubmed:15351195) [from MIM:157640; 2019.02.19]
[PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL DOMINANT 3; PEOA3](https://omim.org/entry/609286)
[TWINKLE mtDNA HELICASE; TWNK](https://omim.org/entry/606075)
PEOA3 is caused by heterozygous mutation in the TWNK mtDNA-helicase gene. [from MIM:609286; 2018.04.20]
The TWNK gene encodes a hexameric DNA helicase which unwinds short stretches of double-stranded DNA in the 5' to 3' direction and, along with mitochondrial single-stranded DNA binding protein and mtDNA polymerase gamma, is thought to play a key role in mtDNA replication. [Gene Cards, TWNK; 2018.04.20]
The TWNK gene encodes 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 (summary by Spelbrink et al., 2001; pubmed:11431692). [from MIM:606075; 2018.04.20]
One to one: 1 human to 1 Drosophila
Moderate- to high-scoring ortholog of human TWNK gene (1 Drosophila to 1 human); Dmel\mtDNA-helicase shares 40% identity and 57% similarity with the human gene.
