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Human DNA Polymerase Gamma Mutation Database

References

All inquiries, additions to the list, and comments should be made to Bill Copeland.

  1. Adachi, Y., Kurihara, S. et al. (2002).  A Japanese Family with Autosomal Dominant Progress External Ophthalmoplegia caused by POLG Mutation.  J Neurol Sci 199, S47.
  2. Agostino, A., Valletta, L., Chinnery, P.F., Ferrari, G., Carrara, F., Taylor, R.W., Schaefer, A.M., Turnbull, D.M., Tiranti, V., and Zeviani, M. (2003). Mutations of ANT1, Twinkle, and POLG1 in sporadic progressive external ophthalmoplegia (PEO). Neurology 60, 1354-1356.
  3. Aknin-Seifer, I.E., Touraine, R.L., Lejeune, H., Jimenez, C., Chouteau, J., Siffroi, J.P., McElreavey, K., Bienvenu, T., Patrat, C., and Levy, R. (2005). Is the CAG repeat of mitochondrial DNA polymerase gamma (POLG) associated with male infertility? A multi-centre French study. Hum Reprod 20, 736-740.
  4. Ashley, N., O'Rourke, A., Smith, C., Adams, S., Gowda, V., Zeviani, M., Brown, G.K., Fratter, C., and Poulton, J.  (2008). Depletion of mitochondrial DNA in fibroblast cultures from patients with POLG1 mutations is a consequence of catalytic mutations.  Hum Mol Genet. May
  5. Barthelemy, C., de Baulny, H.O., and Lombes, A. (2002). D-loop mutations in mitochondrial DNA: link with mitochondrial DNA depletion? Hum Genet 110, 479-487.
  6. Baruffini, E., Lodi, T., Dallabona, C., Puglisi, A., Zeviani, M., and Ferrero, I. (2006). Genetic and chemical rescue of the Saccharomyces cerevisiae phenotype induced by mitochondrial DNA polymerase mutations associated with progressive external ophthalmoplegia in humans. Hum Mol Genet 15, 2846-2855.
  7. Brusco, A., Michielotto, C., Gatta, V., Foresta, C., Matullo, G., Zeviani, M., Ferrari, G., Dragone, E., Calabrese, G., Rossato, M., et al. (2006). The polymorphic polyglutamine repeat in the mitochondrial DNA polymerase gamma gene is not associated with oligozoospermia. J Endocrinol Invest 29, 1-4.
  8. Chan, S.S.L., Longley, M.J., and Copeland, W.C. (2005a). The common A467T mutation in the human mitochondrial DNA polymerase (POLG) compromises catalytic efficiency and interaction with the accessory subunit. J Biol Chem 280, 31341-31346.
  9. Chan, S.S.L., Longley, M.J., and Copeland, W.C. (2006). Modulation of the W748S mutation in DNA polymerase {gamma} by the E1143G polymorphism in mitochondrial disorders. Hum Mol Genet 15, 3473-3483.
  10. Chan, S.S.L., Longley, M.J., Naviaux, R.K., and Copeland, W.C. (2005b). Mono-allelic POLG expression resulting from nonsense-mediated decay and alternative splicing in a patient with Alpers syndrome. DNA Repair 4, 1381-1389.
  11. Davidzon, G., Greene, P., Mancuso, M., Klos, K.J., Ahlskog, J.E., Hirano, M., and Dimauro, S. (2006). Early-onset familial parkinsonism due to POLG mutations. Ann Neurol 59, 859-862.
  12. Davidzon, G., Mancuso, M., Ferraris, S., Quinzii, C., Hirano, M., Peters, H.L., Kirby, D., Thorburn, D.R., and Dimauro, S. (2005). POLG mutations and Alpers syndrome. Ann Neurol 57, 921-923.
  13. e Vries, M.C., Rodenburg, R.J., Morava, E., van Kaauwen, E.P., Ter Laak, H., Mullaart, R.A., Snoeck, I.N., van Hasselt, P.M., Harding, P., van den Heuvel, L.P., et al. (2006). Multiple oxidative phosphorylation deficiencies in severe childhood multi-system disorders due to polymerase gamma (POLG1) mutations. Eur J Pediatr.
  14. Del Bo, R., Bordoni, A., Sciacco, M., Di Fonzo, A., Galbiati, S., Crimi, M., Bresolin, N., and Comi, G.P. (2003). Remarkable infidelity of polymerase gammaA associated with mutations in POLG1 exonuclease domain. Neurology 61, 903-908.
  15. Deschauer, M., Tennant, S., Rokicka, A., He, L., Kraya, T., Turnbull, D.M., Zierz, S., and Taylor, R.W. (2007). MELAS Associated with Mutations in the POLG1 Gene. Neurology 68.
  16. Di Fonzo, A., Bordoni, A., Crimi, M., Sara, G., Bo, R.D., Bresolin, N., and Comi, G.P. (2003). POLG mutations in sporadic mitochondrial disorders with multiple mtDNA deletions. Hum Mutat 22, 498-499.
  17. Ferrari, G., Lamantea, E., Donati, A., Filosto, M., Briem, E., Carrara, F., Parini, R., Simonati, A., Santer, R., and Zeviani, M. (2005). Infantile hepatocerebral syndromes associated with mutations in the mitochondrial DNA polymerase-{gamma}A. Brain 128, 723-731.
  18. Filosto, M., Mancuso, M., Nishigaki, Y., Pancrudo, J., Harati, Y., Gooch, C., Mankodi, A., Bayne, L., Bonilla, E., Shanske, S., et al. (2003). Clinical and genetic heterogeneity in progressive external ophthalmoplegia due to mutations in polymerase gamma. Arch Neurol 60, 1279-1284.
  19. Gago, M.F., Rosas, M.J., Guimaraes, J., Ferreira, M., Vilarinho, L., Castro, L., and Carpenter, S. (2006). SANDO: Two novel mutations in POLG1 gene. Neuromuscul Disord 16, 507-509.
  20. GeneSNPs (2004). SNP Card for POLG (NIEHS, Univerisity of Utah Genome Center), pp. http://www.genome.utah.edu/genesnps/.
  21. Gonzalez-Vioque, E., Blazquez, A., Fernandez-Moreira, D., Bornstein, B., Bautista, J., Arpa, J., Navarro, C., Campos, Y., Fernandez-Moreno, M.A., Garesse, R., et al. (2006). Association of novel POLG mutations and multiple mitochondrial DNA deletions with variable clinical phenotypes in a Spanish population. Arch Neurol 63, 107-111.
  22. Graziewicz, M.A., Longley, M.J., Bienstock, R.J., Zeviani, M., and Copeland, W.C. (2004). Structure-function defects of human mitochondrial DNA polymerase in autosomal dominant progressive external ophthalmoplegia. Nat Struct Mol Biol 11, 770-776.
  23. Hakonen, A.H., Heiskanen, S., Juvonen, V., Lappalainen, I., Luoma, P.T., Rantamaki, M., Goethem, G.V., Lofgren, A., Hackman, P., Paetau, A., et al. (2005). Mitochondrial DNA polymerase W748S mutation: a common cause of autosomal recessive ataxia with ancient European origin. Am J Hum Genet 77, 430-441.
  24. Harris, T.P., Gomas, K.P., Weir, F., Holyoake, A.J., McHugh, P., Wu, M., Sin, Y., Sin, I.L., and Sin, F.Y. (2006). Molecular analysis of polymerase gamma gene and mitochondrial polymorphism in fertile and subfertile men. Int J Androl 29, 421-433.
  25. Harrower, T., Stewart, J. D., Hudson, G., Houlden, H., Warner, G., O'Donovan, D. G., Findlay, L., Taylor, R. W. De Silva, R., and Chinnery, P. F. (2008).  POLG1 mutations manifesting as autosomal recessive axonal Charcot-Marie-Tooth disease.  Arch. Neurol 65, 133-136.
  26. Hisama, F.M., Mancuso, M., Filosto, M., and DiMauro, S. (2005). Progressive external ophthalmoplegia: a new family with tremor and peripheral neuropathy. Am J Med Genet A 135, 217-219.
  27. Horvath, R., Hudson, G., Ferrari, G., Futterer, N., Ahola, S., Lamantea, E., Prokisch, H., Lochmuller, H., McFarland, R., Ramesh, V., et al. (2006). Phenotypic spectrum associated with mutations of the mitochondrial polymerase {gamma} gene. Brain 129, 1674-1684.
  28. Invernizzi, F., Varanese, S., Thomas, A., Carrara, F., Onofrj, M., Zeviani, M. (2008) Two novel POLG1 mutations in a patient with progressive external ophthalmoplegia, levodopa-responsive pseudo-orthostatic tremor and parkinsonism. Neuromuscular Disorders In press.
  29. Hudson, G., Deschauer, M., Taylor, R.W., Hanna, M.G., Fialho, D., Schaefer, A.M., He, L.-P., Blakely, E., Turnbull, D.M., and Chinnery, P.F. (2006a). POLG1, C10ORF2 & ANT1 mutations are uncommon in sporadic PEO with multiple mtDNA deletions. Neurology 66, 1439-1441.
  30. Hudson, G., Schaefer, A.M., Taylor, R.W., Tiangyou, W., Gibson, A., Venables, G., Griffiths, P., Burn, D.J., Turnbull, D.M., and Chinnery, P.F. (2006b). Mutation of the linker-region of POLG1 associated with PEO and parkinsonism. Neurology In press.
  31. Jensen, M., Leffers, H., Petersen, J.H., Nyboe Andersen, A., Jorgensen, N., Carlsen, E., Jensen, T.K., Skakkebaek, N.E., and Rajpert-De Meyts, E. (2004). Frequent polymorphism of the mitochondrial DNA polymerase gamma gene (POLG) in patients with normal spermiograms and unexplained subfertility. Hum Reprod 19, 65-70.
  32. Kollberg, G., Jansson, M., Perez-Bercoff, A., Melberg, A., Lindberg, C., Holme, E., Moslemi, A.R., and Oldfors, A. (2005). Low frequency of mtDNA point mutations in patients with PEO associated with POLG1 mutations. Eur J Hum Genet 13, 463-469.
  33. Kollberg, G., Moslemi, A.R., Darin, N., Nennesmo, I., Bjarnadottir, I., Uvebrant, P., Holme, E., Melberg, A., Tulinius, M., and Oldfors, A. (2006). POLG1 Mutations Associated With Progressive Encephalopathy in Childhood. J Neuropathol Exp Neurol 65, 758-768.
  34. Krausz, C., Guarducci, E., Becherini, L., Degl'Innocenti, S., Gerace, L., Balercia, G., and Forti, G. (2004). The clinical significance of the POLG gene polymorphism in male infertility. J Clin Endocrinol Metab 89, 4292-4297.
  35. Lamantea, E., Tiranti, V., Bordoni, A., Toscano, A., Bono, F., Servidei, S., Papadimitriou, A., Spelbrink, H., Silvestri, L., Casari, G., et al. (2002). Mutations of mitochondrial DNA polymerase gamma are a frequent cause of autosomal dominant or recessive Progressive External Ophthalmoplegia. Ann Neurol 52, 211-219.
  36. Lamantea, E., and Zeviani, M. (2004). Sequence analysis of familial PEO shows additional mutations associated with the 752C-->T and 3527C-->T changes in the POLG1 gene. Ann Neurol 56, 454-455.
  37. Lewis, W., Day, B.J., Kohler, J.J., Hosseini, S.H., Chan, S.S.L., Green, E., Haase, C.P., Keebaugh, E., Long, R., Ludaway, T., et al. (2007). MtDNA depletion, oxidative stress, cardiomyopathy, and death from transgenic cardiac targeted human mutant polymerase gamma. J Clin Invest 87, 326-335.
  38. Luoma, P., Melberg, A., Rinne, J.O., Kaukonen, J.A., Nupponen, N.N., Chalmers, R.M., Oldfors, P.A., Rautakorpi, I., Peltonen, P.L., Majamaa, P.K., et al. (2004). Parkinsonism, premature menopause, and mitochondrial DNA polymerase gamma mutations: clinical and molecular genetic study. Lancet 364, 875-882.
  39. Luoma, P.T., Eerola, J., Ahola, S., Hakonen, A.H., Hellstrom, O., Kivisto, K.T., Tienari, P.J., and Suomalainen, A. (2007). Mitochondrial DNA polymerase gamma variants in idiopathic sporadic Parkinson disease. Neurology 69, 1152-1159.
  40. Luoma, P.T., Luo, N., Loscher, W.N., Farr, C.L., Horvath, R., Wanschitz, J., Kiechl, S., Kaguni, L.S., and Suomalainen, A. (2005). Functional defects due to spacer-region mutations of human mitochondrial DNA polymerase in a family with an ataxia-myopathy syndrome. Hum Mol Genet 14, 1907-1920.
  41. Malyarchuk, B.A., Papuga, M., Grzybowski, T., Rogozin, I.B., Wozniak, M., Derenko, M.V., Rychkov, S.Y., Czarny, J., Zakharov, I.A., and Miscicka-Sliwka, D. (2005). Low variability of the POLG (CAG)n repeat in north Eurasian populations. Hum Biol 77, 355-365.
  42. Mancuso, M., Filosto, M., Bellan, M., Liguori, R., Montagna, P., Baruzzi, A., DiMauro, S., and Carelli, V. (2004a). POLG mutations causing ophthalmoplegia, sensorimotor polyneuropathy, ataxia, and deafness. Neurology 62, 316-318.
  43. Mancuso, M., Filosto, M., Oh, S.J., and DiMauro, S. (2004b). A novel polymerase gamma mutation in a family with ophthalmoplegia, neuropathy, and Parkinsonism. Arch Neurol 61, 1777-1779.
  44. McFarland, R., Hudson, G., Taylor, R.W., Green, S.H., Hodges, S., McKiernan, P.J., Chinnery, P.F., Ramesh, V. (2008).  Reversible valproate hepatotoxicity due to mutatuions in mitochondrial DNA polyermase gamma(POLG1).  Arch Dis Child 93, 151-153.
  45. Melberg, A., Nennesmo, I., Moslemi, A.R., Kollberg, G., Luoma, P., Suomalainen, A., Holme, E., and Oldfors, A. (2005). Alzheimer pathology associated with POLG1 mutation, multiple mtDNA deletions, and APOE4/4: premature ageing or just coincidence? Acta Neuropathol (Berl) 110, 315-316.
  46. Naimi, M., Bannwarth, S., Procaccio, V., Pouget, J., Desnuelle, C., Pellissier, J.F., Rotig, A., Munnich, A., Calvas, P., Richelme, C., et al. (2006). Molecular analysis of ANT1, TWINKLE and POLG in patients with multiple deletions or depletion of mitochondrial DNA by a dHPLC-based assay. Eur J Hum Genet.
  47. Naviaux, R.K., and Nguyen, K.V. (2004). POLG Mutations associated with Alpers' Syndrome and Mitochondrial DNA Depletion. Ann Neurol 55, 706-712.
  48. Naviaux, R.K., and Nguyen, K.V. (2005). POLG Mutations associated with Alpers' Syndrome and Mitochondrial DNA Depletion. Ann Neurol 58, 491.
  49. Nguyen, K.V., Ostergaard, E., Ravn, S.H., Balslev, T., Danielsen, E.R., Vardag, A., McKiernan, P.J., Gray, G., and Naviaux, R.K. (2005). POLG Mutations in Alpers Syndrome. Neurology 65, 1493-1495.
  50. Nguyen, K.V., Sharief, F., Chan, S.S.L., Copeland, W.C., and Naviaux, R.K. (2006). Molecular Diagnosis of Alpers Syndrome. J Hepatology 45, 108-116.
  51. Nowak, R., Zub, R., Skoneczna, I., Sikora, K., and Ligaj, M. (2005). CAG repeat polymorphism in the DNA polymerase {gamma} gene in a Polish population: an association with testicular cancer risk. Ann Oncol 16, 1211-1212.
  52. Pagnamenta, A.T., Taanman, J.W., Wilson, C.J., Anderson, N.E., Marotta, R., Duncan, A.J., Bitner-Glindzicz, M., Taylor, R.W., Laskowski, A., Thorburn, D.R., et al. (2006). Dominant inheritance of premature ovarian failure associated with mutant mitochondrial DNA polymerase gamma. Hum Reprod 21, 2467-2473.
  53. Ponamarev, M.V., Longley, M.J., Nguyen, D., Kunkel, T.A., and Copeland, W.C. (2002). Active Site Mutation in DNA Polymerase gamma Associated with Progressive External Ophthalmoplegia Causes Error-prone DNA Synthesis. J Biol Chem 277, 15225-15228.
  54. Reichenbach, J., Schubert, R., Horvath, R., Petersen, J., Futterer, N., Malle, E., Stumpf, A., Gebhardt, B.R., Koehl, U., Schraven, B., et al. (2006). Fatal neonatal-onset mitochondrial respiratory chain disease with T cell immunodeficiency. Pediatr Res 60, 321-326.
  55. Ropp, P.A., and Copeland, W.C. (1996). Cloning and characterization of the human mitochondrial DNA polymerase, DNA polymerase gamma. Genomics 36, 449-458.
  56. 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., et al. (2001). Mutations at the mitochondrial DNA polymerase (POLG) locus associated with male infertility. Nat Genet 29, 261-262.
  57. Santoro, L., Manganelli, F., Lanzillo, R., Tessa, A., Barbieri, F., Pierelli, F., Di Giacinto, G., Nigro, V., and Santorelli, F.M. (2006). A new POLG1 mutation with peo and severe axonal and demyelinating sensory-motor neuropathy. J Neurol 253, 869-874.
  58. Stopinska, K., Grzybowski, T., Malyarchuk, B.A., Derenko, M.V., and Miscicka-Sliwka, D. (2006). Optimization of the Y831C mutation detection in human DNA polymerase gamma by allelic discrimination assay. Acta Biochim Pol 53, 591-593.
  59. Stuart, G.R., Santos, J.H., Strand, M.K., Van Houten, B., and Copeland, W.C. (2006). Mitochondrial DNA defects in S. cerevisiae with mutations in DNA polymerase gamma associated with Progressive External Ophthalmolplegia. Hum Mol Genet 15, 363-374.
  60. Tiangyou, W., Hudson, G., Ghezzi, D., Ferrari, G., Zeviani, M., Burn, D.J., and Chinnery, P.F. (2006). POLG1 in idiopathic Parkinson disease. Neurology 67, 1698-1700.
  61. Tzoulis, C., Engelsen, B.A., Telstad, W., Aasly, J., Zeviani, M., Winterthun, S., Ferrari, G., Aarseth, J.H., and Bindoff, L.A. (2006). The spectrum of clinical disease caused by the A467T and W748S POLG mutations: a study of 26 cases. Brain 129, 1685-1692.
  62. Uusimaa, J., Hinttala, R., Rantala, H., Paivarinta, M., Herva, R., Roytta, M., Soini, H., Moilanen, J., Remes, A., Hassinen, I., and Majamaa, K. (2008).  Homozygous W748S mutation in the POLGI gene in patients with juvenile-onset Alpers syndrome and status epilepticus.  Epilepsia 1-8.
  63. Van Goethem, G., Dermaut, B., Lofgren, A., Martin, J.J., and Van Broeckhoven, C. (2001). Mutation of POLG is associated with progressive external ophthalmoplegia characterized by mtDNA deletions. Nat Genet 28, 211-212.
  64. Van Goethem, G., Luoma, P., Rantamaki, M., Al Memar, A., Kaakkola, S., Hackman, P., Krahe, R., Lofgren, A., Martin, J.J., De Jonghe, P., et al. (2004). POLG mutations in neurodegenerative disorders with ataxia but no muscle involvement. Neurology 63, 1251-1257.
  65. Van Goethem, G., Martin, J.J., Dermaut, B., Lofgren, A., Wibail, A., Ververken, D., Tack, P., Dehaene, I., Van Zandijcke, M., Moonen, M., et al. (2003a). Recessive POLG mutations presenting with sensory and ataxic neuropathy in compound heterozygote patients with progressive external ophthalmoplegia. Neuromuscul Disord 13, 133-142.
  66. Van Goethem, G., Mercelis, R., Lofgren, A., Seneca, S., Ceuterick, C., Martin, J.J., and Van Broeckhoven, C. (2003b). Patient homozygous for a recessive POLG mutation presents with features of MERRF. Neurology 61, 1811-1813.
  67. Van Goethem, G., Schwartz, M., Lofgren, A., Dermaut, B., Van Broeckhoven, C., and Vissing, J. (2003c). Novel POLG mutations in progressive external ophthalmoplegia mimicking mitochondrial neurogastrointestinal encephalomyopathy. Eur J Hum Genet 11, 547-549.
  68. Wanrooij, S., Luoma, P., van Goethem, G., van Broeckhoven, C., Suomalainen, A., and Spelbrink, J.N. (2004). Twinkle and POLG defects enhance age-dependent accumulation of mutations in the control region of mtDNA. Nucleic Acids Res 32, 3053-3064.
  69. Wiltshire, E., Davidzon, G., DiMauro, S.,  Ackman, H., Sadleir, L., Haas, L., Zuccollo, J., McEwen, A., and Thorburn, D. R. (2008). Juvenile Alpers Disease. Archives of Neurology, 65, 121-124.
  70. Winterthun, S., Ferrari, G., He, L., Taylor, R.W., Zeviani, M., Turnbull, D.M., Engelsen, B.A., Moen, G., and Bindoff, L.A. (2005). Autosomal recessive mitochondrial ataxic syndrome due to mitochondrial polymerase gamma mutations. Neurology 64, 1204-1208.
  71. Wong, L., Naviaux, R., Brunetti-Pierri, N., Zhang, Q., Schmitt, E., Truong, C., Milone, M., Cohen, B., Wical, B., Ganesh, J., Basinger, A., Burton, B., Swoboda, K., Gilbert, D., Vanderver, A., Saneto, R., Maranda, B., Arnold, G., Abdenur, J., Waters, P., Copeland, W. (2008).  Molecular and clinical genetics of mitochondrial diseases due to POLG mutations.  Human Mutations. In press
  72. Yamanaka, H., Gatanaga, H., Kosalaraksa, P., Matsuoka-Aizawa, S., Takahashi, T., Kimura, S., and Oka, S. (2007). Novel Mutation of Human DNA Polymerase gamma Associated with Mitochondrial Toxicity Induced by Anti-HIV Treatment. J Infect Dis 195, 1419-1425.
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Last Reviewed: 7 April 2006