This report describes PEOA4, a subtype of progressive external ophthalmoplegia with mitochondrial DNA deletions; PEOA4 exhibits autosomal dominant inheritance. The human gene implicated in this disease is POLG2, which encodes an accessory subunit of DNA polymerase gamma (DNA polγ), the polymerase that replicates mitochondrial DNA. A number of diseases that are characterized by accumulation of defects in mitochondrial DNA are associated with mutations in one of the subunits of DNA pol&ggr: a 140-kD catalytic subunit (POLG; see FBhh0000432) and a 55-kD accessory subunit (POLG2). This report describes work done in Drosophila characterizing phenotypes of the fly ortholog of POLG2, PolG2. Classical loss-of-function mutations, RNAi-targeting constructs, and and allele caused by insertional mutagenesis have been generated for Dmel\PolG2.
The human POLG2 gene has not been introduced into flies.
Animals homozygous for loss-of-function mutations of PolG2 die during the pupal stage. Mitochondrial DNA (mtDNA) depletion is observed in larval muscle and brain; reduced cell proliferation in the brain is observed; larval locomotion is mildly affected. The impact of mtDNA depletion on mitochondrial and synaptic vesicle precursor transport in axons has been assessed; due to compensatory transport flux and increased mitochondrial density, the transport profiles of mitochondria and synaptic vesicle precursors change very little.
[updated Oct. 2020 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 4; PEOA4](https://omim.org/entry/610131)
[POLYMERASE, DNA, GAMMA-2; POLG2](https://omim.org/entry/604983)
Progressive external ophthalmoplegia-4 is an autosomal dominant form of mitochondrial disease that variably affects skeletal muscle, the nervous system, the liver, and the gastrointestinal tract. Age at onset ranges from infancy to adulthood. The phenotype ranges from relatively mild, with adult-onset skeletal muscle weakness and weakness of the external eye muscles, to severe, with a multisystem disorder characterized by delayed psychomotor development, lactic acidosis, constipation, and liver involvement (summary by Young et al., 2011; pubmed:21555342). [from MIM:610131; 2018.08.22]
PEOA4 is caused by heterozygous mutation in the nuclear-encoded DNA polymerase gamma-2 gene (POLG2). [from MIM:610131; 2018.08.22]
mtDNA is replicated by DNA polymerase gamma, which is composed of a 140-kD catalytic subunit (POLG) and a 55-kD accessory subunit (POLG2). [from MIM:604983; 2018.08.22]
One to one: 1 human to 1 Drosophila.
Moderate-scoring ortholog of human POLG2 (1 Drosophila to 1 human); Dmel\DNApol-γ35 shares 24% identity and 37% similarity with the human gene.
