8d3r

Structural highlights

Disease

DPOG1_HUMAN Defects in POLG are the cause of progressive external ophthalmoplegia with mitochondrial DNA deletions autosomal dominant type 1 (PEOA1) [MIM:157640. Progressive external ophthalmoplegia is characterized by progressive weakness of ocular muscles and levator muscle of the upper eyelid. In a minority of cases, it is associated with skeletal myopathy, which predominantly involves axial or proximal muscles and which causes abnormal fatigability and even permanent muscle weakness. Ragged-red fibers and atrophy are found on muscle biopsy. A large proportion of chronic ophthalmoplegias are associated with other symptoms, leading to a multisystemic pattern of this disease. Additional symptoms are variable, and may include cataracts, hearing loss, sensory axonal neuropathy, ataxia, depression, hypogonadism, and parkinsonism.^{[1] [2] [3] [4] [5] [6]} Defects in POLG are a cause of progressive external ophthalmoplegia with mitochondrial DNA deletions autosomal recessive (PEOB) [MIM:258450. PEOB is a severe form of progressive external ophthalmoplegia. It is clinically more heterogeneous than the autosomal dominant forms. Can be more severe.^{[7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20]} Defects in POLG are a cause of sensory ataxic neuropathy dysarthria and ophthalmoparesis (SANDO) [MIM:607459. SANDO is a systemic disorder resulting from mitochondrial dysfunction associated with mitochondrial depletion in skeletal muscle and peripheral nerve tissue. The clinical triad of symptoms consists of sensory ataxic neuropathy, dysarthria, and ophthalmoparesis. However, the phenotype varies widely, even within the same family, and can also include myopathy, seizures, and hearing loss. An atypical form of the disease is characterized by headaches and/or seizures manifesting in childhood or adolescence, followed by development of cerebellar and sensory ataxia, dysarthria, progressive external ophthalmoplegia, and myoclonus in early adulthood.^{[21] [22] [23] [24] [25] [26] [27] [28] [29]} Defects in POLG are the cause of mitochondrial DNA depletion syndrome type 4A (MTDPS4A) [MIM:203700; also called Alpers diffuse degeneration of cerebral gray matter with hepatic cirrhosis. An autosomal recessive hepatocerebral syndrome. The typical course of the disease includes severe developmental delay, intractable seizures, liver failure, and death in childhood. Refractory seizures, cortical blindness, progressive liver dysfunction, and acute liver failure after exposure to valproic acid are considered diagnostic features. The neuropathological hallmarks are neuronal loss, spongiform degeneration, and astrocytosis of the visual cortex. Liver biopsy results show steatosis, often progressing to cirrhosis.^{[30] [31] [32] [33] [34] [35]} Defects in POLG are the cause of mitochondrial DNA depletion syndrome type 4B (MTDPS4B) [MIM:613662; also known as mitochondrial DNA depletion syndrome 4B MNGIE type or mitochondrial neurogastrointestinal encephalopathy syndrome POLG-related. An autosomal recessive progressive multisystem disorder clinically characterized by chronic gastrointestinal dysmotility and pseudo-obstruction, cachexia, progressive external ophthalmoplegia, axonal sensory ataxic neuropathy, and muscle weakness. Defects in POLG are a cause of Leigh syndrome (LS) [MIM:256000. LS is a severe neurological disorder characterized by bilaterally symmetrical necrotic lesions in subcortical brain regions.^[36]

Function

DPOG1_HUMAN Involved in the replication of mitochondrial DNA. Associates with mitochondrial DNA.

References

1. ↑ Lamantea E, Tiranti V, Bordoni A, Toscano A, Bono F, Servidei S, Papadimitriou A, Spelbrink H, Silvestri L, Casari G, Comi GP, Zeviani M. Mutations of mitochondrial DNA polymerase gammaA are a frequent cause of autosomal dominant or recessive progressive external ophthalmoplegia. Ann Neurol. 2002 Aug;52(2):211-9. PMID:12210792 doi:10.1002/ana.10278
2. ↑ Ponamarev MV, Longley MJ, Nguyen D, Kunkel TA, Copeland WC. Active site mutation in DNA polymerase gamma associated with progressive external ophthalmoplegia causes error-prone DNA synthesis. J Biol Chem. 2002 May 3;277(18):15225-8. Epub 2002 Mar 15. PMID:11897778 doi:10.1074/jbc.C200100200
3. ↑ Mancuso M, Filosto M, Oh SJ, DiMauro S. A novel polymerase gamma mutation in a family with ophthalmoplegia, neuropathy, and Parkinsonism. Arch Neurol. 2004 Nov;61(11):1777-9. PMID:15534189 doi:10.1001/archneur.61.11.1777
4. ↑ Luoma P, Melberg A, Rinne JO, Kaukonen JA, Nupponen NN, Chalmers RM, Oldfors A, Rautakorpi I, Peltonen L, Majamaa K, Somer H, Suomalainen A. Parkinsonism, premature menopause, and mitochondrial DNA polymerase gamma mutations: clinical and molecular genetic study. Lancet. 2004 Sep 4-10;364(9437):875-82. PMID:15351195 doi:10.1016/S0140-6736(04)16983-3
5. ↑ Hudson G, Schaefer AM, Taylor RW, Tiangyou W, Gibson A, Venables G, Griffiths P, Burn DJ, Turnbull DM, Chinnery PF. Mutation of the linker region of the polymerase gamma-1 (POLG1) gene associated with progressive external ophthalmoplegia and Parkinsonism. Arch Neurol. 2007 Apr;64(4):553-7. PMID:17420318 doi:10.1001/archneur.64.4.553
6. ↑ Virgilio R, Ronchi D, Hadjigeorgiou GM, Bordoni A, Saladino F, Moggio M, Adobbati L, Kafetsouli D, Tsironi E, Previtali S, Papadimitriou A, Bresolin N, Comi GP. Novel Twinkle (PEO1) gene mutations in mendelian progressive external ophthalmoplegia. J Neurol. 2008 Sep;255(9):1384-91. doi: 10.1007/s00415-008-0926-3. Epub 2008 Jun , 30. PMID:18575922 doi:10.1007/s00415-008-0926-3
7. ↑ Luoma P, Melberg A, Rinne JO, Kaukonen JA, Nupponen NN, Chalmers RM, Oldfors A, Rautakorpi I, Peltonen L, Majamaa K, Somer H, Suomalainen A. Parkinsonism, premature menopause, and mitochondrial DNA polymerase gamma mutations: clinical and molecular genetic study. Lancet. 2004 Sep 4-10;364(9437):875-82. PMID:15351195 doi:10.1016/S0140-6736(04)16983-3
8. ↑ 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 Jul;28(3):211-2. PMID:11431686 doi:10.1038/90034
9. ↑ Filosto M, Mancuso M, Nishigaki Y, Pancrudo J, Harati Y, Gooch C, Mankodi A, Bayne L, Bonilla E, Shanske S, Hirano M, DiMauro S. Clinical and genetic heterogeneity in progressive external ophthalmoplegia due to mutations in polymerase gamma. Arch Neurol. 2003 Sep;60(9):1279-84. PMID:12975295 doi:http://dx.doi.org/10.1001/archneur.60.9.1279
10. ↑ Van Goethem G, Lofgren A, Dermaut B, Ceuterick C, Martin JJ, Van Broeckhoven C. Digenic progressive external ophthalmoplegia in a sporadic patient: recessive mutations in POLG and C10orf2/Twinkle. Hum Mutat. 2003 Aug;22(2):175-6. PMID:12872260 doi:10.1002/humu.10246
11. ↑ Di Fonzo A, Bordoni A, Crimi M, Sara G, Del Bo R, Bresolin N, Comi GP. POLG mutations in sporadic mitochondrial disorders with multiple mtDNA deletions. Hum Mutat. 2003 Dec;22(6):498-9. PMID:14635118 doi:10.1002/humu.9203
12. ↑ Agostino A, Valletta L, Chinnery PF, Ferrari G, Carrara F, Taylor RW, Schaefer AM, Turnbull DM, Tiranti V, Zeviani M. Mutations of ANT1, Twinkle, and POLG1 in sporadic progressive external ophthalmoplegia (PEO). Neurology. 2003 Apr 22;60(8):1354-6. PMID:12707443
13. ↑ Van Goethem G, Martin JJ, Dermaut B, Lofgren A, Wibail A, Ververken D, Tack P, Dehaene I, Van Zandijcke M, Moonen M, Ceuterick C, De Jonghe P, Van Broeckhoven C. Recessive POLG mutations presenting with sensory and ataxic neuropathy in compound heterozygote patients with progressive external ophthalmoplegia. Neuromuscul Disord. 2003 Feb;13(2):133-42. PMID:12565911
14. ↑ Lamantea E, Zeviani M. Sequence analysis of familial PEO shows additional mutations associated with the 752C-->T and 3527C-->T changes in the POLG1 gene. Ann Neurol. 2004 Sep;56(3):454-5. PMID:15349879 doi:10.1002/ana.20219
15. ↑ Van Goethem G, Luoma P, Rantamaki M, Al Memar A, Kaakkola S, Hackman P, Krahe R, Lofgren A, Martin JJ, De Jonghe P, Suomalainen A, Udd B, Van Broeckhoven C. POLG mutations in neurodegenerative disorders with ataxia but no muscle involvement. Neurology. 2004 Oct 12;63(7):1251-7. PMID:15477547
16. ↑ Luoma PT, Luo N, Loscher WN, Farr CL, Horvath R, Wanschitz J, Kiechl S, Kaguni LS, Suomalainen A. Functional defects due to spacer-region mutations of human mitochondrial DNA polymerase in a family with an ataxia-myopathy syndrome. Hum Mol Genet. 2005 Jul 15;14(14):1907-20. Epub 2005 May 25. PMID:15917273 doi:10.1093/hmg/ddi196
17. ↑ Davidzon G, Greene P, Mancuso M, Klos KJ, Ahlskog JE, Hirano M, DiMauro S. Early-onset familial parkinsonism due to POLG mutations. Ann Neurol. 2006 May;59(5):859-62. PMID:16634032 doi:10.1002/ana.20831
18. ↑ Gonzalez-Vioque E, Blazquez A, Fernandez-Moreira D, Bornstein B, Bautista J, Arpa J, Navarro C, Campos Y, Fernandez-Moreno MA, Garesse R, Arenas J, Martin MA. Association of novel POLG mutations and multiple mitochondrial DNA deletions with variable clinical phenotypes in a Spanish population. Arch Neurol. 2006 Jan;63(1):107-11. PMID:16401742 doi:10.1001/archneur.63.1.107
19. ↑ Horvath R, Hudson G, Ferrari G, Futterer N, Ahola S, Lamantea E, Prokisch H, Lochmuller H, McFarland R, Ramesh V, Klopstock T, Freisinger P, Salvi F, Mayr JA, Santer R, Tesarova M, Zeman J, Udd B, Taylor RW, Turnbull D, Hanna M, Fialho D, Suomalainen A, Zeviani M, Chinnery PF. Phenotypic spectrum associated with mutations of the mitochondrial polymerase gamma gene. Brain. 2006 Jul;129(Pt 7):1674-84. Epub 2006 Apr 18. PMID:16621917 doi:10.1093/brain/awl088
20. ↑ Naimi M, Bannwarth S, Procaccio V, Pouget J, Desnuelle C, Pellissier JF, Rotig A, Munnich A, Calvas P, Richelme C, Jonveaux P, Castelnovo G, Simon M, Clanet M, Wallace D, Paquis-Flucklinger V. 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. 2006 Aug;14(8):917-22. Epub 2006 Apr 26. PMID:16639411 doi:10.1038/sj.ejhg.5201627
21. ↑ Van Goethem G, Martin JJ, Dermaut B, Lofgren A, Wibail A, Ververken D, Tack P, Dehaene I, Van Zandijcke M, Moonen M, Ceuterick C, De Jonghe P, Van Broeckhoven C. Recessive POLG mutations presenting with sensory and ataxic neuropathy in compound heterozygote patients with progressive external ophthalmoplegia. Neuromuscul Disord. 2003 Feb;13(2):133-42. PMID:12565911
22. ↑ Van Goethem G, Luoma P, Rantamaki M, Al Memar A, Kaakkola S, Hackman P, Krahe R, Lofgren A, Martin JJ, De Jonghe P, Suomalainen A, Udd B, Van Broeckhoven C. POLG mutations in neurodegenerative disorders with ataxia but no muscle involvement. Neurology. 2004 Oct 12;63(7):1251-7. PMID:15477547
23. ↑ Luoma PT, Luo N, Loscher WN, Farr CL, Horvath R, Wanschitz J, Kiechl S, Kaguni LS, Suomalainen A. Functional defects due to spacer-region mutations of human mitochondrial DNA polymerase in a family with an ataxia-myopathy syndrome. Hum Mol Genet. 2005 Jul 15;14(14):1907-20. Epub 2005 May 25. PMID:15917273 doi:10.1093/hmg/ddi196
24. ↑ Horvath R, Hudson G, Ferrari G, Futterer N, Ahola S, Lamantea E, Prokisch H, Lochmuller H, McFarland R, Ramesh V, Klopstock T, Freisinger P, Salvi F, Mayr JA, Santer R, Tesarova M, Zeman J, Udd B, Taylor RW, Turnbull D, Hanna M, Fialho D, Suomalainen A, Zeviani M, Chinnery PF. Phenotypic spectrum associated with mutations of the mitochondrial polymerase gamma gene. Brain. 2006 Jul;129(Pt 7):1674-84. Epub 2006 Apr 18. PMID:16621917 doi:10.1093/brain/awl088
25. ↑ Naimi M, Bannwarth S, Procaccio V, Pouget J, Desnuelle C, Pellissier JF, Rotig A, Munnich A, Calvas P, Richelme C, Jonveaux P, Castelnovo G, Simon M, Clanet M, Wallace D, Paquis-Flucklinger V. 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. 2006 Aug;14(8):917-22. Epub 2006 Apr 26. PMID:16639411 doi:10.1038/sj.ejhg.5201627
26. ↑ Mancuso M, Filosto M, Bellan M, Liguori R, Montagna P, Baruzzi A, DiMauro S, Carelli V. POLG mutations causing ophthalmoplegia, sensorimotor polyneuropathy, ataxia, and deafness. Neurology. 2004 Jan 27;62(2):316-8. PMID:14745080
27. ↑ Hakonen AH, Heiskanen S, Juvonen V, Lappalainen I, Luoma PT, Rantamaki M, Goethem GV, Lofgren A, Hackman P, Paetau A, Kaakkola S, Majamaa K, Varilo T, Udd B, Kaariainen H, Bindoff LA, Suomalainen A. Mitochondrial DNA polymerase W748S mutation: a common cause of autosomal recessive ataxia with ancient European origin. Am J Hum Genet. 2005 Sep;77(3):430-41. Epub 2005 Jul 27. PMID:16080118 doi:S0002-9297(07)63023-7
28. ↑ Winterthun S, Ferrari G, He L, Taylor RW, Zeviani M, Turnbull DM, Engelsen BA, Moen G, Bindoff LA. Autosomal recessive mitochondrial ataxic syndrome due to mitochondrial polymerase gamma mutations. Neurology. 2005 Apr 12;64(7):1204-8. PMID:15824347 doi:64/7/1204
29. ↑ Gago MF, Rosas MJ, Guimaraes J, Ferreira M, Vilarinho L, Castro L, Carpenter S. SANDO: two novel mutations in POLG1 gene. Neuromuscul Disord. 2006 Aug;16(8):507-9. Epub 2006 Aug 21. PMID:16919951 doi:10.1016/j.nmd.2006.05.016
30. ↑ Horvath R, Hudson G, Ferrari G, Futterer N, Ahola S, Lamantea E, Prokisch H, Lochmuller H, McFarland R, Ramesh V, Klopstock T, Freisinger P, Salvi F, Mayr JA, Santer R, Tesarova M, Zeman J, Udd B, Taylor RW, Turnbull D, Hanna M, Fialho D, Suomalainen A, Zeviani M, Chinnery PF. Phenotypic spectrum associated with mutations of the mitochondrial polymerase gamma gene. Brain. 2006 Jul;129(Pt 7):1674-84. Epub 2006 Apr 18. PMID:16621917 doi:10.1093/brain/awl088
31. ↑ Naimi M, Bannwarth S, Procaccio V, Pouget J, Desnuelle C, Pellissier JF, Rotig A, Munnich A, Calvas P, Richelme C, Jonveaux P, Castelnovo G, Simon M, Clanet M, Wallace D, Paquis-Flucklinger V. 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. 2006 Aug;14(8):917-22. Epub 2006 Apr 26. PMID:16639411 doi:10.1038/sj.ejhg.5201627
32. ↑ Naviaux RK, Nguyen KV. POLG mutations associated with Alpers' syndrome and mitochondrial DNA depletion. Ann Neurol. 2004 May;55(5):706-12. PMID:15122711 doi:10.1002/ana.20079
33. ↑ Davidzon G, Mancuso M, Ferraris S, Quinzii C, Hirano M, Peters HL, Kirby D, Thorburn DR, DiMauro S. POLG mutations and Alpers syndrome. Ann Neurol. 2005 Jun;57(6):921-3. PMID:15929042 doi:10.1002/ana.20498
34. ↑ Ferrari G, Lamantea E, Donati A, Filosto M, Briem E, Carrara F, Parini R, Simonati A, Santer R, Zeviani M. Infantile hepatocerebral syndromes associated with mutations in the mitochondrial DNA polymerase-gammaA. Brain. 2005 Apr;128(Pt 4):723-31. Epub 2005 Feb 2. PMID:15689359 doi:10.1093/brain/awh410
35. ↑ Taanman JW, Rahman S, Pagnamenta AT, Morris AA, Bitner-Glindzicz M, Wolf NI, Leonard JV, Clayton PT, Schapira AH. Analysis of mutant DNA polymerase gamma in patients with mitochondrial DNA depletion. Hum Mutat. 2009 Feb;30(2):248-54. doi: 10.1002/humu.20852. PMID:18828154 doi:10.1002/humu.20852
36. ↑ Taanman JW, Rahman S, Pagnamenta AT, Morris AA, Bitner-Glindzicz M, Wolf NI, Leonard JV, Clayton PT, Schapira AH. Analysis of mutant DNA polymerase gamma in patients with mitochondrial DNA depletion. Hum Mutat. 2009 Feb;30(2):248-54. doi: 10.1002/humu.20852. PMID:18828154 doi:10.1002/humu.20852
37. ↑ Park J, Herrmann GK, Mitchell PG, Sherman MB, Yin YW. Polγ coordinates DNA synthesis and proofreading to ensure mitochondrial genome integrity. Nat Struct Mol Biol. 2023 Jun;30(6):812-823. PMID:37202477 doi:10.1038/s41594-023-00980-2