Diseases of DNA Polymerase Gamma

  • Omar Hikmat
  • Pirjo Isohanni
  • Anu Suomalainen
  • Laurence A. BindoffEmail author


Polymerase gamma (Polγ) is the DNA-dependent DNA polymerase responsible for replicating mitochondrial DNA. The enzyme is a trimer and comprises one catalytic subunit (POLG), which contains the polymerase activity together with proofreading exonuclease activity, and two accessory subunits (POLG2) that promote DNA binding and processivity. Replication of mtDNA requires several additional proteins: in vitro studies have shown that the minimal replication machinery consists of the helicase Twinkle, mitochondrial RNA polymerase and single-stranded binding protein [1], but others may be required in vivo [2]. Mutations in POLG are one of the most common causes of mitochondrial disease and responsible for a wide range of phenotypes. Mutations in POLG2 are rare. Disease caused by mutations in Twinkle gives a similar spectrum of disease to those caused by POLG and we will discuss them together where this is appropriate.


  1. 1.
    Korhonen JA, Pham XH, Pellegrini M, Falkenberg M. Reconstitution of a minimal mtDNA replisome in vitro. EMBO J. 2004;23(12):2423–9.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Wanrooij S, Falkenberg M. The human mitochondrial replication fork in health and disease. Biochim Biophys Acta. 2010;1797(8):1378–88.PubMedCrossRefGoogle Scholar
  3. 3.
    Tzoulis C, Neckelmann G, Mork SJ, Engelsen BE, Viscomi C, Moen G, et al. Localized cerebral energy failure in DNA polymerase gamma-associated encephalopathy syndromes. Brain J Neurol. 2010;133(Pt 5):1428–37.CrossRefGoogle Scholar
  4. 4.
    Muller-Hocker J, Horvath R, Schafer S, Hessel H, Muller-Felber W, Kuhr J, et al. Mitochondrial DNA depletion and fatal infantile hepatic failure due to mutations in the mitochondrial polymerase gamma (POLG) gene: a combined morphological/enzyme histochemical and immunocytochemical/biochemical and molecular genetic study. J Cell Mol Med. 2011;15(2):445–56.PubMedCrossRefGoogle Scholar
  5. 5.
    Hudson G, Chinnery PF. Mitochondrial DNA polymerase-gamma and human disease. Hum Mol Genet. 2006;15(2):R244–52.PubMedCrossRefGoogle Scholar
  6. 6.
    Saneto RP, Naviaux RK. Polymerase gamma disease through the ages. Dev Disabil Res Rev. 2010;16(2):163–74.PubMedCrossRefGoogle Scholar
  7. 7.
    Van Goethem G, Dermaut B, Lofgren A, Martin JJ, Van Broeckhoven C. Mutation of POLG is associated with progressive external ophthalmoplegia characterized by mtDNA deletions. Nat Genet. 2001;28(3):211–2.PubMedCrossRefGoogle Scholar
  8. 8.
    Winterthun S, Ferrari G, He L, Taylor RW, Zeviani M, Turnbull DM, et al. Autosomal recessive mitochondrial ataxic syndrome due to mitochondrial polymerase gamma mutations. Neurology. 2005;64(7):1204–8.PubMedCrossRefGoogle Scholar
  9. 9.
    Tzoulis C, Engelsen BA, Telstad W, Aasly J, Zeviani M, Winterthun S, et al. The spectrum of clinical disease caused by the A467T and W748S POLG mutations: a study of 26 cases. Brain J Neurol. 2006;129(Pt 7):1685–92.CrossRefGoogle Scholar
  10. 10.
    Hakonen AH, Heiskanen S, Juvonen V, Lappalainen I, Luoma PT, Rantamaki M, et al. Mitochondrial DNA polymerase W748S mutation: a common cause of autosomal recessive ataxia with ancient European origin. Am J Hum Genet. 2005;77(3):430–41.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Hikmat O, Tzoulis C, Chong WK, Chentouf L, Klingenberg C, Fratter C, et al. The clinical spectrum and natural history of early-onset diseases due to DNA polymerase gamma mutations. Genet Med. 2017;19(11):1217–25.PubMedCrossRefGoogle Scholar
  12. 12.
    Nguyen KV, Sharief FS, Chan SS, Copeland WC, Naviaux RK. Molecular diagnosis of Alpers syndrome. J Hepatol. 2006;45(1):108–16.PubMedCrossRefGoogle Scholar
  13. 13.
    Cohen BH, Chinnery PF, Copeland WC. POLG-related disorders. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, LJH B, et al., editors. GeneReviews(R). Seattle (WA): University of Washington; 1993.Google Scholar
  14. 14.
    Harding BN. Progressive neuronal degeneration of childhood with liver disease (Alpers-Huttenlocher syndrome): a personal review. J Child Neurol. 1990;5(4):273–87.PubMedCrossRefGoogle Scholar
  15. 15.
    Alpers BJ. DIffuse progressive degeneration of the gray matter of the cerebrum. Arch Neurol Psychiatr. 1931;25(3):469–505.CrossRefGoogle Scholar
  16. 16.
    Naviaux RK, Nyhan WL, Barshop BA, Poulton J, Markusic D, Karpinski NC, et al. Mitochondrial DNA polymerase gamma deficiency and mtDNA depletion in a child with Alpers’ syndrome. Ann Neurol. 1999;45(1):54–8.PubMedCrossRefGoogle Scholar
  17. 17.
    Naviaux RK, Nguyen KV. POLG mutations associated with Alpers’ syndrome and mitochondrial DNA depletion. Ann Neurol. 2004;55(5):706–12.PubMedCrossRefGoogle Scholar
  18. 18.
    Uusimaa J, Hinttala R, Rantala H, Paivarinta M, Herva R, Roytta M, et al. Homozygous W748S mutation in the POLG1 gene in patients with juvenile-onset Alpers syndrome and status epilepticus. Epilepsia. 2008;49(6):1038–45.PubMedCrossRefGoogle Scholar
  19. 19.
    Engelsen BA, Tzoulis C, Karlsen B, Lillebo A, Laegreid LM, Aasly J, et al. POLG1 mutations cause a syndromic epilepsy with occipital lobe predilection. Brain J Neurol. 2008;131(Pt 3):818–28.CrossRefGoogle Scholar
  20. 20.
    Wolf NI, Rahman S, Schmitt B, Taanman JW, Duncan AJ, Harting I, et al. Status epilepticus in children with Alpers’ disease caused by POLG1 mutations: EEG and MRI features. Epilepsia. 2009;50(6):1596–607.PubMedCrossRefGoogle Scholar
  21. 21.
    Bindoff LA, Engelsen BA. Mitochondrial diseases and epilepsy. Epilepsia. 2012;53(Suppl 4):92–7.PubMedCrossRefGoogle Scholar
  22. 22.
    Saneto RP, Cohen BH, Copeland WC, Naviaux RK. Alpers-Huttenlocher syndrome. Pediatr Neurol. 2013;48(3):167–78.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    de Vries MC, Rodenburg RJ, Morava E, van Kaauwen EP, ter Laak H, Mullaart RA, et al. Multiple oxidative phosphorylation deficiencies in severe childhood multi-system disorders due to polymerase gamma (POLG1) mutations. Eur J Pediatr. 2007;166(3):229–34.PubMedCrossRefGoogle Scholar
  24. 24.
    Horvath R, Hudson G, Ferrari G, Futterer N, Ahola S, Lamantea E, et al. Phenotypic spectrum associated with mutations of the mitochondrial polymerase gamma gene. Brain J Neurol. 2006;129(Pt 7):1674–84.CrossRefGoogle Scholar
  25. 25.
    Saneto RP, Lee IC, Koenig MK, Bao X, Weng SW, Naviaux RK, et al. POLG DNA testing as an emerging standard of care before instituting valproic acid therapy for pediatric seizure disorders. Seizure. 2010;19(3):140–6.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Taanman JW, Rahman S, Pagnamenta AT, Morris AA, Bitner-Glindzicz M, Wolf NI, et al. Analysis of mutant DNA polymerase gamma in patients with mitochondrial DNA depletion. Hum Mutat. 2009;30(2):248–54.PubMedCrossRefGoogle Scholar
  27. 27.
    Anagnostou ME, Ng YS, Taylor RW, McFarland R. Epilepsy due to mutations in the mitochondrial polymerase gamma (POLG) gene: a clinical and molecular genetic review. Epilepsia. 2016;57(10):1531–45.PubMedCrossRefGoogle Scholar
  28. 28.
    Hikmat O, Eichele T, Tzoulis C, Bindoff LA. Understanding the epilepsy in POLG related disease. Int J Mol Sci. 2017;18(9):E1845.PubMedCrossRefGoogle Scholar
  29. 29.
    Janssen W, Quaegebeur A, Van Goethem G, Ann L, Smets K, Vandenberghe R, et al. The spectrum of epilepsy caused by POLG mutations. Acta Neurol Belg. 2016;116(1):17–25.PubMedCrossRefGoogle Scholar
  30. 30.
    Luoma P, Melberg A, Rinne JO, Kaukonen JA, Nupponen NN, Chalmers RM, et al. Parkinsonism, premature menopause, and mitochondrial DNA polymerase gamma mutations: clinical and molecular genetic study. Lancet (London, England). 2004;364(9437):875–82.CrossRefGoogle Scholar
  31. 31.
    Hakonen AH, Davidzon G, Salemi R, Bindoff LA, Van Goethem G, Dimauro S, et al. Abundance of the POLG disease mutations in Europe, Australia, New Zealand, and the United States explained by single ancient European founders. Eur J Hum Genet. 2007;15(7):779–83.PubMedCrossRefGoogle Scholar
  32. 32.
    Deschauer M, Tennant S, Rokicka A, He L, Kraya T, Turnbull DM, et al. MELAS associated with mutations in the POLG1 gene. Neurology. 2007;68(20):1741–2.PubMedCrossRefGoogle Scholar
  33. 33.
    Van Goethem G, Schwartz M, Lofgren A, Dermaut B, Van Broeckhoven C, Vissing J. Novel POLG mutations in progressive external ophthalmoplegia mimicking mitochondrial neurogastrointestinal encephalomyopathy. Eur J Hum Genet. 2003;11(7):547–9.PubMedCrossRefGoogle Scholar
  34. 34.
    Pagnamenta AT, Taanman JW, Wilson CJ, Anderson NE, Marotta R, Duncan AJ, et al. Dominant inheritance of premature ovarian failure associated with mutant mitochondrial DNA polymerase gamma. Hum Reprod. 2006;21(10):2467–73.PubMedCrossRefGoogle Scholar
  35. 35.
    Wong LJ, Naviaux RK, Brunetti-Pierri N, Zhang Q, Schmitt ES, Truong C, et al. Molecular and clinical genetics of mitochondrial diseases due to POLG mutations. Hum Mutat. 2008;29(9):E150–72.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Milone M, Brunetti-Pierri N, Tang LY, Kumar N, Mezei MM, Josephs K, et al. Sensory ataxic neuropathy with ophthalmoparesis caused by POLG mutations. Neuromuscul Disord. 2008;18(8):626–32.PubMedCrossRefGoogle Scholar
  37. 37.
    Pitceathly RD, Tomlinson SE, Hargreaves I, Bhardwaj N, Holton JL, Morrow JM, et al. Distal myopathy with cachexia: an unrecognised phenotype caused by dominantly-inherited mitochondrial polymerase gamma mutations. J Neurol Neurosurg Psychiatry. 2013;84(1):107–10.PubMedCrossRefGoogle Scholar
  38. 38.
    Davidzon G, Greene P, Mancuso M, Klos KJ, Ahlskog JE, Hirano M, et al. Early-onset familial parkinsonism due to POLG mutations. Ann Neurol. 2006;59(5):859–62.PubMedCrossRefGoogle Scholar
  39. 39.
    Nowak R, Zub R, Skoneczna I, Sikora K, Ligaj M. CAG repeat polymorphism in the DNA polymerase gamma gene in a Polish population: an association with testicular cancer risk. Ann Oncol. 2005;16(7):1211–2.PubMedCrossRefGoogle Scholar
  40. 40.
    Van Goethem G, Luoma P, Rantamaki M, Al Memar A, Kaakkola S, Hackman P, et al. POLG mutations in neurodegenerative disorders with ataxia but no muscle involvement. Neurology. 2004;63(7):1251–7.PubMedCrossRefGoogle Scholar
  41. 41.
    Suomalainen A, Majander A, Haltia M, Somer H, Lonnqvist J, Savontaus ML, et al. Multiple deletions of mitochondrial DNA in several tissues of a patient with severe retarded depression and familial progressive external ophthalmoplegia. J Clin Invest. 1992;90(1):61–6.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Suomalainen A, Majander A, Wallin M, Setala K, Kontula K, Leinonen H, et al. Autosomal dominant progressive external ophthalmoplegia with multiple deletions of mtDNA: clinical, biochemical, and molecular genetic features of the 10q-linked disease. Neurology. 1997;48(5):1244–53.PubMedCrossRefGoogle Scholar
  43. 43.
    Spelbrink JN, Li FY, Tiranti V, Nikali K, Yuan QP, Tariq M, et al. Human mitochondrial DNA deletions associated with mutations in the gene encoding Twinkle, a phage T7 gene 4-like protein localized in mitochondria. Nat Genet. 2001;28(3):223–31.PubMedCrossRefGoogle Scholar
  44. 44.
    Hudson G, Deschauer M, Busse K, Zierz S, Chinnery PF. Sensory ataxic neuropathy due to a novel C10Orf2 mutation with probable germline mosaicism. Neurology. 2005;64(2):371–3.PubMedCrossRefGoogle Scholar
  45. 45.
    Koskinen T, Santavuori P, Sainio K, Lappi M, Kallio AK, Pihko H. Infantile onset spinocerebellar ataxia with sensory neuropathy: a new inherited disease. J Neurol Sci. 1994;121(1):50–6.PubMedCrossRefGoogle Scholar
  46. 46.
    Nikali K, Suomalainen A, Saharinen J, Kuokkanen M, Spelbrink JN, Lonnqvist T, et al. Infantile onset spinocerebellar ataxia is caused by recessive mutations in mitochondrial proteins Twinkle and Twinky. Hum Mol Genet. 2005;14(20):2981–90.PubMedCrossRefGoogle Scholar
  47. 47.
    Lonnqvist T, Paetau A, Valanne L, Pihko H. Recessive twinkle mutations cause severe epileptic encephalopathy. Brain J Neurol. 2009;132(Pt 6):1553–62.CrossRefGoogle Scholar
  48. 48.
    Hakonen AH, Isohanni P, Paetau A, Herva R, Suomalainen A, Lonnqvist T. Recessive Twinkle mutations in early onset encephalopathy with mtDNA depletion. Brain J Neurol. 2007;130(Pt 11):3032–40.CrossRefGoogle Scholar
  49. 49.
    Sarzi E, Goffart S, Serre V, Chretien D, Slama A, Munnich A, et al. Twinkle helicase (PEO1) gene mutation causes mitochondrial DNA depletion. Ann Neurol. 2007;62(6):579–87.PubMedCrossRefGoogle Scholar
  50. 50.
    Morino H, Pierce SB, Matsuda Y, Walsh T, Ohsawa R, Newby M, et al. Mutations in Twinkle primase-helicase cause Perrault syndrome with neurologic features. Neurology. 2014;83(22):2054–61.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Debray FG, Mitchell GA, Allard P, Robinson BH, Hanley JA, Lambert M. Diagnostic accuracy of blood lactate-to-pyruvate molar ratio in the differential diagnosis of congenital lactic acidosis. Clin Chem. 2007;53(5):916–21.PubMedCrossRefGoogle Scholar
  52. 52.
    Chow SL, Rooney ZJ, Cleary MA, Clayton PT, Leonard JV. The significance of elevated CSF lactate. Arch Dis Child. 2005;90(11):1188–9.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Suomalainen A, Elo JM, Pietilainen KH, Hakonen AH, Sevastianova K, Korpela M, et al. FGF-21 as a biomarker for muscle-manifesting mitochondrial respiratory chain deficiencies: a diagnostic study. Lancet Neurol. 2011;10(9):806–18.PubMedCrossRefGoogle Scholar
  54. 54.
    Yatsuga S, Fujita Y, Ishii A, Fukumoto Y, Arahata H, Kakuma T, et al. Growth differentiation factor 15 as a useful biomarker for mitochondrial disorders. Ann Neurol. 2015;78(5):814–23.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Hikmat O, Naess K, Engvall M, Klingenberg C, Rasmussen M, Tallaksen CME, et al. Elevated cerebrospinal fluid protein in POLG-related epilepsy: diagnostic and prognostic implications. Epilepsia. 2018;59(8):1595–602.PubMedCrossRefGoogle Scholar
  56. 56.
    Menezes MP, Rahman S, Bhattacharya K, Clark D, Christodoulou J, Ellaway C, et al. Neurophysiological profile of peripheral neuropathy associated with childhood mitochondrial disease. Mitochondrion. 2016;30:162–7.PubMedCrossRefGoogle Scholar
  57. 57.
    Horga A, Pitceathly RD, Blake JC, Woodward CE, Zapater P, Fratter C, et al. Peripheral neuropathy predicts nuclear gene defect in patients with mitochondrial ophthalmoplegia. Brain J Neurol. 2014;137(Pt 12):3200–12.CrossRefGoogle Scholar
  58. 58.
    Isohanni P, Hakonen AH, Euro L, Paetau I, Linnankivi T, Liukkonen E, et al. POLG1 manifestations in childhood. Neurology. 2011;76(9):811–5.PubMedCrossRefGoogle Scholar
  59. 59.
    Siibak T, Clemente P, Bratic A, Bruhn H, Kauppila TES, Macao B, et al. A multi-systemic mitochondrial disorder due to a dominant p.Y955H disease variant in DNA polymerase gamma. Hum Mol Genet. 2017;26(13):2515–25.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Pruss H, Holtkamp M. Ketamine successfully terminates malignant status epilepticus. Epilepsy Res. 2008;82(2–3):219–22.PubMedCrossRefGoogle Scholar
  61. 61.
    Visser NA, Braun KPJ, Leijten FSS, van Nieuwenhuizen O, Wokke JHJ, van den Bergh WM. Magnesium treatment for patients with refractory status epilepticus due to POLG1-mutations. J Neurol. 2011;258(2):218–22.PubMedCrossRefGoogle Scholar
  62. 62.
    Lupashko S, Malik S, Donahue D, Hernandez A, Perry MS. Palliative functional hemispherectomy for treatment of refractory status epilepticus associated with Alpers’ disease. Childs Nerv Syst. 2011;27(8):1321–3.PubMedCrossRefGoogle Scholar
  63. 63.
    Ng YS, van Ruiten H, Lai HM, Scott R, Ramesh V, Horridge K, et al. The adjunctive application of transcranial direct current stimulation in the management of de novo refractory epilepsia partialis continua in adolescent-onset POLG-related mitochondrial disease. Epilepsia Open. 2018;3(1):103–8.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Martikainen MH, Paivarinta M, Jaaskelainen S, Majamaa K. Successful treatment of POLG-related mitochondrial epilepsy with antiepileptic drugs and low glycaemic index diet. Epileptic Disord. 2012;14(4):438–41.PubMedGoogle Scholar
  65. 65.
    Pfeffer G, Horvath R, Klopstock T, Mootha VK, Suomalainen A, Koene S, et al. New treatments for mitochondrial disease-no time to drop our standards. Nat Rev Neurol. 2013;9(8):474–81.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    McFarland R, Hudson G, Taylor RW, Green SH, Hodges S, McKiernan PJ, et al. Reversible valproate hepatotoxicity due to mutations in mitochondrial DNA polymerase gamma (POLG1). Arch Dis Child. 2008;93(2):151–3.PubMedCrossRefGoogle Scholar
  67. 67.
    Thomson MA, Lynch S, Strong R, Shepherd RW, Marsh W. Orthotopic liver transplantation with poor neurologic outcome in valproate-associated liver failure: a need for critical risk-benefit appraisal in the use of valproate. Transplant Proc. 2000;32(1):200–3.PubMedCrossRefGoogle Scholar
  68. 68.
    Mindikoglu AL, King D, Magder LS, Ozolek JA, Mazariegos GV, Shneider BL. Valproic acid-associated acute liver failure in children: case report and analysis of liver transplantation outcomes in the United States. J Pediatr. 2011;158(5):802–7.PubMedCrossRefGoogle Scholar
  69. 69.
    Kelly DA. Liver transplantation: to do or not to do? Pediatr Transplant. 2000;4(3):170–2.PubMedCrossRefGoogle Scholar
  70. 70.
    Parikh S, Karaa A, Goldstein A, Ng YS, Gorman G, Feigenbaum A, et al. Solid organ transplantation in primary mitochondrial disease: proceed with caution. Mol Genet Metab. 2016;118(3):178–84.PubMedCrossRefGoogle Scholar
  71. 71.
    Hynynen J, Komulainen T, Tukiainen E, Nordin A, Arola J, Kalviainen R, et al. Acute liver failure after valproate exposure in patients with POLG1 mutations and the prognosis after liver transplantation. Liver Transpl. 2014;20(11):1402–12.PubMedCrossRefGoogle Scholar
  72. 72.
    Park S, Kang HC, Lee JS, Park YN, Kim S, Koh H. Alpers-Huttenlocher syndrome first presented with hepatic failure: can liver transplantation be considered as treatment option? Pediatr Gastroenterol Hepatol Nutr. 2017;20(4):259–62.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Martikainen MH, Ng YS, Gorman GS, Alston CL, Blakely EL, Schaefer AM, et al. Clinical, genetic, and radiological features of extrapyramidal movement disorders in mitochondrial disease. JAMA Neurol. 2016;73(6):668–74.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Omar Hikmat
    • 1
    • 2
  • Pirjo Isohanni
    • 3
    • 4
  • Anu Suomalainen
    • 4
    • 5
  • Laurence A. Bindoff
    • 2
    • 6
    Email author
  1. 1.Department of PediatricsHaukeland University HospitalBergenNorway
  2. 2.Department of Clinical Medicine (K1)University of BergenBergenNorway
  3. 3.Department of Child Neurology, Children’s HospitalUniversity of Helsinki and Helsinki University HospitalHelsinkiFinland
  4. 4.Research Programs Unit, Molecular NeurologyBiomedicum Helsinki, University of HelsinkiHelsinkiFinland
  5. 5.Neuroscience CenterUniversity of HelsinkiHelsinkiFinland
  6. 6.Department of NeurologyHaukeland University HospitalBergenNorway

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