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FB2026_01
,
released March 12, 2026
A number of diseases characterized by accumulation of defects in mitochondrial DNA are associated with the human gene POLG (DNA polymerase gamma, catalytic subunit). See links in 'Related Diseases' for information on specific diseases. The POLG protein plays a role in replication of mitochondrial DNA and has both elongation (polymerase) and proofreading (exonuclease) activities. There is a single fly ortholog, PolG1, for which classical loss-of-function alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated.
The human POLG gene has not been introduced into flies.
Animals that are homozygous for loss-of-function alleles of Dmel\PolG1 die before the end of the larval stage. Targeted knockdown effected by RNAi in cholinergic, serotonergic and dopaminergic neurons allows survival to adulthood; lowered respiratory chain activity, premature aging, age-related motor deficits are observed. This system has been used to assess genetic interactions and therapeutic options. For information on genetic interactions, see the PolG1 gene report.
Experiments characterizing mutations in the fly gene analogous to variants implicated in POLG-related disorders include two implicated in progressive external ophthalmoplegia with mtDNA deletions, autosomal dominant 1 (PEOA1). Variant(s) implicated in human disease tested (as analogous mutation in fly gene): Y873C in the fly PolG1 gene (corresponds to Y955C in the human POLG gene); Y873H in the fly PolG1 gene (corresponds to Y955H in the human POLG gene).
Using the Dmel\PolG1 gene, phylogenetically conserved amino acids have been changed and the resulting mutant alleles introduced into flies by recombination in place of the wild-type PolG1 gene. Targeted mutations: D263A in fly, corresponding to D274 in human (affecting exonuclease function); Q1009A in fly, corresponding to Q1102 in human; H1038A in fly, corresponding to H1134 in human (affecting polymerase function). A notable finding is that pol(-) and exo(-) mutations exhibit complementation in trans, supporting a dynamic model in which the polymerase protein moves on and off the template, allowing separation of proofreading and elongation functions.
[updated Oct. 2018 by FlyBase; FBrf0222196]
POLG-related disorders comprise a continuum of overlapping phenotypes; onset ranges from infancy to late adulthood (Gene Reviews, POLG-Related Disorders; 2016.11.16). See links to related diseases, below.
Although typically recessive, at least one POLG-related disorder exhibits semi-dominant inheritance. [from MIM:174763; 2016.11.16]
Mutations affecting the pol domain lead to mitochondrial depletion; mutations affecting the exo domain result in accumulation of random point mutations and small lesions in the mtDNA. (FBrf0232350).
A recently developed resource evaluates the pathogenicity of both previously reported and novel mutations of POLG; 176 unique point mutations had been reported at the date of publication (Nurminen et al., 2017; pubmed:28480171).
The POLG protein is composed of a C-terminal polymerase ('pol') domain and an amino-terminal exonuclease ('exo') domain. The exo domain increases the fidelity of mitochondrial DNA replication by conferring a proofreading activity to the enzyme (Lamantea et al., 2002; 12210792 ). Del Bo et al. (2003; pubmed:14557557) presented evidence suggesting that mutations in the exonuclease domain result in a high frequency of rare, randomly distributed mtDNA point mutations. [from MIM:174763; 2016.11.16]
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.
Ortholog of human POLG (1 Drosophila to 1 human). Dmel\PolG1 shares 44% identity and 58% similarity with human POLG.