Abstract
Mutations in the progressive external ophthalmoplegia 1 (PEO1), adenine nucleotide translocator 1 (ANT1) and DNA polymerase gamma (POLG) genes were reported in patients with progressive external ophthalmoplegia and parkinsonism. However, the genotype–phenotype correlation and pathophysiology of these syndromes are still unknown. In order to define the molecular basis of progressive external ophthalmoplegia and parkinsonism, we screened for mutations in PEO1, ANT1, POLG genes and the whole mitochondrial genome in two families. In results, we identified a compound heterozygous POLG substitutions, c.830A>T (p.H277L) and c.2827C>T (p.R943C) in one of the families. These two mutations in the coding region of POLG alter conserved amino acids in the exonuclease and polymerase domains, respectively, of the POLG protein. Neither of these substitutions was found in the 100 chromosomes of ethnically matched control subjects. In the other family, no mutations were detected in any of the three genes and the whole mitochondrial genome in the blood sample, although mitochondrial DNA deletions were observed in the muscle biopsy sample. Progressive external ophthalmoplegia and parkinsonism are genetically heterogenous disorders, and part of this syndrome may be caused by mutations in other, unknown genes.
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References
Copeland WC (2008) Inherited mitochondrial diseases of DNA replication. Annu Rev Med 59:131–146
Clayton DA (1982) Replication of animal mitochondrial DNA. Cell 28:693–705
Van Goethem G, Dermaut B, Löfgren A, Martin JJ, Van Broeckhoven C (2001) Mutation of POLG is associated with progressive external ophthalmoplegia characterized by mtDNA deletions. Nat Genet 28:211–212
Luoma P, Melberg A, Rinne JO, Kaukonen JA, Nupponen NN, Chalmers RM, Oldfors A, Rautakorpi I, Peltonen L, Majamaa K, Somer H, Suomalainen A (2004) Parkinsonism, premature menopause, and mitochondrial DNA polymerase gamma mutations: clinical and molecular genetic study. Lancet 364:875–882
Stewart JD, Tennant S, Powell H, Omer S, Morris AA, Roxburgh R, Livingston JH, McFarland R, Turnbull DM, Chinnery PF, Taylor RW (2009) Novel POLG1 mutations associated with neuromuscular and liver phenotypes in adults and children. J Med Genet 46:209–214
Mancuso M, Filosto M, Oh SJ, DiMauro S (2004) A novel polymerase gamma mutation in a family with ophthalmoplegia, neuropathy, and parkinsonism. Arch Neurol 61:1777–1779
Hudson G, Schaefer AM, Taylor RW, Tiangyou W, Gibson A, Venables G, Griffiths P, Burn DJ, Turnbull DM, Chinnery PF (2007) Mutation of the linker region of the polymerase gamma-1 (POLG1) gene associated with progressive external ophthalmoplegia and Parkinsonism. Arch Neurol 64:553–557
Remes AM, Hinttala R, Kärppä M, Soini H, Takalo R, Uusimaa J, Majamaa K (2008) Parkinsonism associated with the homozygous W748S mutation in the POLG1 gene. Parkinsonism Relat Disord 14:652–654
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. Neuromuscul Disord 18:460–464
Baloh RH, Salavaggione E, Milbrandt J, Pestronk A (2007) Familial parkinsonism and ophthalmoplegia from a mutation in the mitochondrial DNA helicase twinkle. Arch Neurol 64:998–1000
Galassi G, Lamantea E, Invernizzi F, Tavani F, Pisano I, Ferrero I, Palmieri L, Zeviani M (2008) Additive effects of POLG1 and ANT1 mutations in a complex encephalomyopathy. Neuromuscul Disord 18:465–470
Filosto M, Mancuso M, Nishigaki Y, Pancrudo J, Harati Y, Gooch C, Mankodi A, Bayne L, Bonilla E, Shanske S, Hirano M, DiMauro S (2003) Clinical and genetic heterogeneity in progressive external ophthalmoplegia due to mutations in polymerase gamma. Arch Neurol 60:1279–1284
Spelbrink JN, Li FY, Tiranti V, Nikali K, Yuan QP, Tariq M, Wanrooij S, Garrido N, Comi G, Morandi L, Santoro L, Toscano A, Fabrizi GM, Somer H, Croxen R, Beeson D, Poulton J, Suomalainen A, Jacobs HT, Zeviani M, Larsson C (2001) Human mitochondrial DNA deletions associated with mutations in the gene encoding Twinkle, a phage T7 gene 4-like protein localized in mitochondria. Nat Genet 28:223–231
Kaukonen J, Juselius JK, Tiranti V, Kyttälä A, Zeviani M, Comi GP, Keränen S, Peltonen L, Suomalainen A (2000) Role of adenine nucleotide translocator 1 in mtDNA maintenance. Science 289:782–785
Ashley N, O’Rourke A, Smith C, Adams S, Gowda V, Zeviani M, Brown GK, Fratter C, Poulton J (2008) Depletion of mitochondrial DNA in fibroblast cultures from patients with POLG1 mutations is a consequence of catalytic mutations. Hum Mol Genet 17:2496–2506
Blok MJ, van den Bosch BJ, Jongen E, Hendrickx A, de Die-Smulders CE, Hoogendijk JE, Brusse E, de Visser M, Poll-The BT, Bierau J, de Coo IF, Smeets HJ (2009) The unfolding clinical spectrum of POLG mutations. J Med Genet 46:776–785
Wong LJ, Naviaux RK, Brunetti-Pierri N, Zhang Q, Schmitt ES, Truong C, Milone M, Cohen BH, Wical B, Ganesh J, Basinger AA, Burton BK, Swoboda K, Gilbert DL, Vanderver A, Saneto RP, Maranda B, Arnold G, Abdenur JE, Waters PJ, Copeland WC (2008) Molecular and clinical genetics of mitochondrial diseases due to POLG mutations. Hum Mutat 29:E150–E172
Stewart JD, Tennant S, Powell H, Pyle A, Blakely EL, He L, Hudson G, Roberts M, du Plessis D (2009) Novel POLG1 mutations associated with neuromuscular and liver phenotypes in adults and children. J Med Genet 46:209–214
Fratter C, Gorman GS, Stewart JD, Buddles M, Smith C, Evans J, Seller A, Poulton J, Roberts M, Hanna MG, Rahman S, Omer SE, Klopstock T, Schoser B, Kornblum C, Czermin B, Lecky B, Blakely EL, Craig K, Chinnery PF, Turnbull DM, Horvath R, Taylor RW (2010) The clinical, histochemical, and molecular spectrum of PEO1 (Twinkle)-linked adPEO. Neurology 74:1619–1626
Winterthun S, Ferrari G, He L, Taylor RW, Taylor RW, Zeviani M, Turnbull DM, Engelsen BA, Moen G, Bindoff LA (2005) Autosomal recessive mitochondrial ataxic syndrome due to mitochondrial polymerase gamma mutations. Neurology 64:1204–1208
Errea JM, Ara JR, Aibar C, de Pedro-Cuesta J (1999) Prevalence of Parkinson’s disease in lower Aragon, Spain. Mov Disord 14:596–604
Harada H, Nishikawa S, Takahashi K (1983) Epidemiology of Parkinson’s disease in a Japanese city. Arch Neurol 40:151–154
Langston JW, Ballard P, Tetrud JW, Irwin I (1983) Chronic parkinsonism in humans due to a product of meperidine-analog synthesis. Science 219:979–980
Miyako K, Irie T, Muta T, Umeda S, Kai Y, Fujiwara T, Takeshige K, Kang D (1999) 1-Methyl-4-phenylpyridinium ion (MPP+) selectively inhibits the replication of mitochondrial DNA. Eur J Biochem 259:412–418
Valente EM, Abou-Sleiman PM, Caputo V, Muqit MM, Harvey K, Gispert S, Ali Z, Del Turco D, Bentivoglio AR, Healy DG, Albanese A, Nussbaum R, González-Maldonado R, Deller T, Salvi S, Cortelli P, Gilks WP, Latchman DS, Harvey RJ, Dallapiccola B, Auburger G, Wood NW (2004) Hereditary early-onset Parkinson’s disease caused by mutations in PINK1. Science 304:1158–1160
Tiangyou W, Hudson G, Ghezzi D, Ferrari G, Zeviani M, Burn DJ, Chinnery PF (2006) POLG1 in idiopathic Parkinson disease. Neurology 67:1698–1700
Hudson G, Tiangyou W, Stutt A, Eccles M, Robinson L, Burn DJ, Chinnery PF (2009) No association between common POLG1 variants and sporadic idiopathic Parkinson’s disease. Mov Disord 24:1092–1094
Human DNA polymerase gamma mutation database. http://www.tools.niehs.nih.gov/polg/
Acknowledgments
We thank all patients and control subjects for their active cooperation. This work was supported in part by a Grant-in-Aid for the Research Committee of CNS Degenerative Diseases of the Research on Measures for Intractable Diseases from the Ministry of Health, Welfare and Labor, Japan, by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports, and Culture, Japan.
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Sato, K., Yabe, I., Yaguchi, H. et al. Genetic analysis of two Japanese families with progressive external ophthalmoplegia and parkinsonism. J Neurol 258, 1327–1332 (2011). https://doi.org/10.1007/s00415-011-5936-x
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DOI: https://doi.org/10.1007/s00415-011-5936-x