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Gene Review

POLG  -  polymerase (DNA directed), gamma

Homo sapiens

Synonyms: DNA polymerase subunit gamma-1, MDP1, MIRAS, MTDPS4A, MTDPS4B, ...
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Disease relevance of POLG


Psychiatry related information on POLG

  • Studies that focused on mood disorder comorbid with somatic symptoms, suggested roles for the mitochondrial DNA (mtDNA) 3644 mutation and the POLG mutation [6].

High impact information on POLG

  • Mutation of POLG is associated with progressive external ophthalmoplegia characterized by mtDNA deletions [7].
  • POLG is the only DNA polymerase responsible for mtDNA replication [7].
  • Analysis of POLG genotypes in different populations identified an association between absence of the common, ten-repeat allele and male infertility typified by a range of sperm quality defects but excluding azoospermia [8].
  • These findings suggest that Dnaja3 is crucial for mitochondrial biogenesis, at least in part, through its chaperone activity on Polga and provide genetic evidence of the necessity for mitochondrial Hsp40 in preventing DCM [9].
  • Recently, we and collaborators reported a new neurodegenerative disorder with autosomal recessive ataxia in four patients homozygous for two amino acid changes in POLG: W748S in cis with E1143G [10].

Chemical compound and disease context of POLG


Biological context of POLG


Anatomical context of POLG

  • By expressing POLG fusion proteins in cultured human cells, we show that the enzyme is targeted to mitochondria, where the Myc epitope-tagged POLG is catalytically active as a DNA polymerase [17].
  • In all subjects, the POLG polymorphism was assessed in relation to their semen quality, and--in the fertile controls--with biological fecundity measured as waiting time-to-pregnancy (TTP) for the couples [18].
  • Comparison between the CAG repeat length distribution of control and Parkinson's disease samples revealed no evidence of either germ line or somatic POLG CAG repeat instability in Parkinson's disease patients [19].
  • Thus, the differential distribution of fibers with extremely high concentrations of mutant mtDNAs characterizes, and probably distinguishes, the skeletal muscle of PEO and MELAS patients harboring the same nt-3243 mutation [20].
  • The neuromuscular signs were PEO, dysarthria, dysphonia, limb muscle weakness with wasting, absence of Achilles tendon reflexes, and distal vibration sensory loss [21].

Associations of POLG with chemical compounds

  • The human nuclear gene for the catalytic subunit of mitochondrial DNA polymerase gamma ( POLG) contains within its coding region a CAG microsatellite encoding a polyglutamine repeat [16].
  • The self-assembly of triblock copolymers of poly(ethylene oxide-b-methyl methacrylate-b-styrene) (PEO-b-PMMA-b-PS), where PS is the major component and PMMA and PEO are minor components, provides a robust route to highly ordered, nanoporous arrays with cylindrical pores of 10-15 nm that show promise in block copolymer lithography [22].
  • Temperature-induced reversible morphological changes of polystyrene-block-poly(ethylene oxide) micelles with degrees of polymerization of 962 for the PS and 227 for the PEO blocks (PS962-b-PEO227) in N,N-dimethylformamide (DMF)/water, in which water is a selective solvent for the PEO block, were observed [23].
  • The distribution, dynamics, and local environments of the TFA-modified titania, PEO, and PPO components of the hybrid were investigated [24].
  • The viscosity-adjustable property of F127 block copolymer PEO99PPO69PEO99, PEO and PPO being poly(ethylene oxide) and poly(propylene oxide), respectively, was found to be useful for the development of automated capillary electrophoresis (CE) [25].

Other interactions of POLG

  • Mutations in POLG can also cause autosomal recessive PEO, which is often associated with multisystemic disorders [26].
  • Molecular analysis of ANT1, TWINKLE and POLG in patients with multiple deletions or depletion of mitochondrial DNA by a dHPLC-based assay [27].
  • In addition, one 'homozygous mutant' was identified in 91 fertile men (1.1%) CONCLUSION: Under our conditions, our study does not confirm any relationship between the polymorphic CAG repeat in the POLG gene and male infertility [28].
  • Analysis of POLG in other primates indicates that the repeat has expanded from a shorter, glutamine-rich sequence, present in the common ancestor of Old and New World monkeys [16].
  • We suggest that abnormal expression of factors such as TFAM and POLG in NT embryos will prematurely drive mtDNA replication, hence impacting on early development [29].

Analytical, diagnostic and therapeutic context of POLG


  1. Mutant POLG2 disrupts DNA polymerase gamma subunits and causes progressive external ophthalmoplegia. Longley, M.J., Clark, S., Yu Wai Man, C., Hudson, G., Durham, S.E., Taylor, R.W., Nightingale, S., Turnbull, D.M., Copeland, W.C., Chinnery, P.F. Am. J. Hum. Genet. (2006) [Pubmed]
  2. ANT1, Twinkle, POLG, and TP: new genes open our eyes to ophthalmoplegia. Hirano, M., DiMauro, S. Neurology (2001) [Pubmed]
  3. POLG mutations in neurodegenerative disorders with ataxia but no muscle involvement. Van Goethem, G., Luoma, P., Rantamäki, M., Al Memar, A., Kaakkola, S., Hackman, P., Krahe, R., Löfgren, A., Martin, J.J., De Jonghe, P., Suomalainen, A., Udd, B., Van Broeckhoven, C. Neurology (2004) [Pubmed]
  4. POLG mutations causing ophthalmoplegia, sensorimotor polyneuropathy, ataxia, and deafness. Mancuso, M., Filosto, M., Bellan, M., Liguori, R., Montagna, P., Baruzzi, A., DiMauro, S., Carelli, V. Neurology (2004) [Pubmed]
  5. POLG1 mutations manifesting as autosomal recessive axonal Charcot-Marie-Tooth disease. Harrower, T., Stewart, J.D., Hudson, G., Houlden, H., Warner, G., O'Donovan, D.G., Findlay, L.J., Taylor, R.W., De Silva, R., Chinnery, P.F. Arch. Neurol. (2008) [Pubmed]
  6. Molecular genetics of bipolar disorder and depression. Kato, T. Psychiatry Clin. Neurosci. (2007) [Pubmed]
  7. Mutation of POLG is associated with progressive external ophthalmoplegia characterized by mtDNA deletions. Van Goethem, G., Dermaut, B., Löfgren, A., Martin, J.J., Van Broeckhoven, C. Nat. Genet. (2001) [Pubmed]
  8. Mutations at the mitochondrial DNA polymerase (POLG) locus associated with male infertility. Rovio, A.T., Marchington, D.R., Donat, S., Schuppe, H.C., Abel, J., Fritsche, E., Elliott, D.J., Laippala, P., Ahola, A.L., McNay, D., Harrison, R.F., Hughes, B., Barrett, T., Bailey, D.M., Mehmet, D., Jequier, A.M., Hargreave, T.B., Kao, S.H., Cummins, J.M., Barton, D.E., Cooke, H.J., Wei, Y.H., Wichmann, L., Poulton, J., Jacobs, H.T. Nat. Genet. (2001) [Pubmed]
  9. A crucial role of mitochondrial Hsp40 in preventing dilated cardiomyopathy. Hayashi, M., Imanaka-Yoshida, K., Yoshida, T., Wood, M., Fearns, C., Tatake, R.J., Lee, J.D. Nat. Med. (2006) [Pubmed]
  10. Mitochondrial DNA polymerase W748S mutation: a common cause of autosomal recessive ataxia with ancient European origin. Hakonen, A.H., Heiskanen, S., Juvonen, V., Lappalainen, I., Luoma, P.T., Rantamaki, M., Goethem, G.V., Lofgren, A., Hackman, P., Paetau, A., Kaakkola, S., Majamaa, K., Varilo, T., Udd, B., Kaariainen, H., Bindoff, L.A., Suomalainen, A. Am. J. Hum. Genet. (2005) [Pubmed]
  11. The expanding phenotype of mitochondrial myopathy. DiMauro, S., Gurgel-Giannetti, J. Curr. Opin. Neurol. (2005) [Pubmed]
  12. Abnormal blood lactate accumulation after exercise in patients with multiple mitochondrial DNA deletions and minor muscular symptoms. Lindholm, H., Löfberg, M., Somer, H., Näveri, H., Sovijärvi, A. Clinical physiology and functional imaging. (2004) [Pubmed]
  13. Association of novel POLG mutations and multiple mitochondrial DNA deletions with variable clinical phenotypes in a Spanish population. González-Vioque, E., Blázquez, A., Fernández-Moreira, D., Bornstein, B., Bautista, J., Arpa, J., Navarro, C., Campos, Y., Fernández-Moreno, M.A., Garesse, R., Arenas, J., Martín, M.A. Arch. Neurol. (2006) [Pubmed]
  14. Recessive POLG mutations presenting with sensory and ataxic neuropathy in compound heterozygote patients with progressive external ophthalmoplegia. Van Goethem, G., Martin, J.J., Dermaut, B., Löfgren, A., Wibail, A., Ververken, D., Tack, P., Dehaene, I., Van Zandijcke, M., Moonen, M., Ceuterick, C., De Jonghe, P., Van Broeckhoven, C. Neuromuscul. Disord. (2003) [Pubmed]
  15. A novel missense adenine nucleotide translocator-1 gene mutation in a Greek adPEO family. Napoli, L., Bordoni, A., Zeviani, M., Hadjigeorgiou, G.M., Sciacco, M., Tiranti, V., Terentiou, A., Moggio, M., Papadimitriou, A., Scarlato, G., Comi, G.P. Neurology (2001) [Pubmed]
  16. A prevalent POLG CAG microsatellite length allele in humans and African great apes. Rovio, A.T., Abel, J., Ahola, A.L., Andres, A.M., Bertranpetit, J., Blancher, A., Bontrop, R.E., Chemnick, L.G., Cooke, H.J., Cummins, J.M., Davis, H.A., Elliott, D.J., Fritsche, E., Hargreave, T.B., Hoffman, S.M., Jequier, A.M., Kao, S.H., Kim, H.S., Marchington, D.R., Mehmet, D., Otting, N., Poulton, J., Ryder, O.A., Schuppe, H.C., Takenaka, O., Wei, Y.H., Wichmann, L., Jacobs, H.T. Mamm. Genome (2004) [Pubmed]
  17. In vivo functional analysis of the human mitochondrial DNA polymerase POLG expressed in cultured human cells. Spelbrink, J.N., Toivonen, J.M., Hakkaart, G.A., Kurkela, J.M., Cooper, H.M., Lehtinen, S.K., Lecrenier, N., Back, J.W., Speijer, D., Foury, F., Jacobs, H.T. J. Biol. Chem. (2000) [Pubmed]
  18. Frequent polymorphism of the mitochondrial DNA polymerase gamma gene (POLG) in patients with normal spermiograms and unexplained subfertility. Jensen, M., Leffers, H., Petersen, J.H., Nyboe Andersen, A., Jørgensen, N., Carlsen, E., Jensen, T.K., Skakkebaek, N.E., Rajpert-De Meyts, E. Hum. Reprod. (2004) [Pubmed]
  19. Analysis of the trinucleotide CAG repeat from the DNA polymerase gamma gene (POLG) in patients with Parkinson's disease. Taanman, J.W., Schapira, A.H. Neurosci. Lett. (2005) [Pubmed]
  20. Extremely high levels of mutant mtDNAs co-localize with cytochrome c oxidase-negative ragged-red fibers in patients harboring a point mutation at nt 3243. Petruzzella, V., Moraes, C.T., Sano, M.C., Bonilla, E., DiMauro, S., Schon, E.A. Hum. Mol. Genet. (1994) [Pubmed]
  21. Muscle-nerve involvement in autosomal dominant progressive external ophthalmoplegia with hypogonadism. Melberg, A., Lundberg, P.O., Henriksson, K.G., Olsson, Y., Stålberg, E. Muscle Nerve (1996) [Pubmed]
  22. Defect-free nanoporous thin films from ABC triblock copolymers. Bang, J., Kim, S.H., Drockenmuller, E., Misner, M.J., Russell, T.P., Hawker, C.J. J. Am. Chem. Soc. (2006) [Pubmed]
  23. Temperature-Induced Reversible Morphological Changes of Polystyrene-block-Poly(ethylene Oxide) Micelles in Solution. Bhargava, P., Tu, Y., Zheng, J.X., Xiong, H., Quirk, R.P., Cheng, S.Z. J. Am. Chem. Soc. (2007) [Pubmed]
  24. Structural analysis of hybrid titania-based mesostructured composites. Boettcher, S.W., Bartl, M.H., Hu, J.G., Stucky, G.D. J. Am. Chem. Soc. (2005) [Pubmed]
  25. Viscosity-adjustable block copolymer for DNA separation by capillary electrophoresis. Wu, C., Liu, T., Chu, B. Electrophoresis (1998) [Pubmed]
  26. Clinical and genetic heterogeneity in progressive external ophthalmoplegia due to mutations in polymerase gamma. Filosto, M., Mancuso, M., Nishigaki, Y., Pancrudo, J., Harati, Y., Gooch, C., Mankodi, A., Bayne, L., Bonilla, E., Shanske, S., Hirano, M., DiMauro, S. Arch. Neurol. (2003) [Pubmed]
  27. Molecular analysis of ANT1, TWINKLE and POLG in patients with multiple deletions or depletion of mitochondrial DNA by a dHPLC-based assay. Naïmi, M., Bannwarth, S., Procaccio, V., Pouget, J., Desnuelle, C., Pellissier, J.F., Rötig, A., Munnich, A., Calvas, P., Richelme, C., Jonveaux, P., Castelnovo, G., Simon, M., Clanet, M., Wallace, D., Paquis-Flucklinger, V. Eur. J. Hum. Genet. (2006) [Pubmed]
  28. Is the CAG repeat of mitochondrial DNA polymerase gamma (POLG) associated with male infertility? A multi-centre French study. Aknin-Seifer, I.E., Touraine, R.L., Lejeune, H., Jimenez, C., Chouteau, J., Siffroi, J.P., McElreavey, K., Bienvenu, T., Patrat, C., Levy, R. Hum. Reprod. (2005) [Pubmed]
  29. Nuclear Transfer: Preservation of a Nuclear Genome at the Expense of Its Associated mtDNA Genome(s). Bowles, E.J., Campbell, K.H., St John, J.C. Curr. Top. Dev. Biol. (2007) [Pubmed]
  30. Localization by fluorescence in situ hybridization (FISH) of human mitochondrial polymerase gamma (POLG) to human chromosome band 15q24-->q26, and of mouse mitochondrial polymerase gamma (Polg) to mouse chromosome band 7E, with confirmation by direct sequence analysis of bacterial artificial chromosomes (BACs). Zullo, S.J., Butler, L., Zahorchak, R.J., Macville, M., Wilkes, C., Merril, C.R. Cytogenet. Cell Genet. (1997) [Pubmed]
  31. Autosomal recessive mitochondrial ataxic syndrome due to mitochondrial polymerase gamma mutations. Winterthun, S., Ferrari, G., He, L., Taylor, R.W., Zeviani, M., Turnbull, D.M., Engelsen, B.A., Moen, G., Bindoff, L.A. Neurology (2005) [Pubmed]
  32. Study of copper sulfide crystallization in PEO-SDS solutions. Orphanou, M., Leontidis, E., Kyprianidou-Leodidou, T., Koutsoukos, P., Kyriacou, K.C. Langmuir : the ACS journal of surfaces and colloids. (2004) [Pubmed]
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