Abstract
POLG gene encodes the catalytic subunit of DNA polymerase gamma, essential for mitochondrial DNA (mtDNA) replication and repair. Mutations in POLG have been linked to a spectrum of clinical phenotypes, resulting in autosomal recessive or dominant mitochondrial diseases. These mutations have been associated with heterogeneous phenotypes, presenting with varying severity and at different ages of onset, ranging from the neonatal period to late adult life. We screened 13 patients for POLG mutations. All patients underwent a complete neurological examination, and in most of cases, muscle biopsy was performed. We detected 15 different variations in 13 unrelated Italian patients. Two mutations were novel and mapped in the pol domain (p.Thr989dup and p.Ala847Thr) of the enzyme. We also report new cases carrying controversial variations previously described as incompletely penetrant or a variant of unknown significance. Our study increases the range of clinical presentations associated with mutations in POLG gene, underlining some peculiar clinical features, such as PEO associated with corneal edema, and epilepsy, severe neuropathy with achalasia. The addition of two new substitutions, including the second report of an in-frame duplication, to the growing list of defects increases the value of POLG genetic diagnosis in a range of neurological presentations.
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References
Copeland WC (2008) Inherited mitochondrial diseases of DNA replication. Annu Rev Med 59:131–146. doi:10.1146/annurev.med.59.053006.104646
Kaguni LS (2004) DNA polymerase gamma, the mitochondrial replicase. Annu Rev Biochem 73:293–320. doi:10.1146/annurev.biochem.72.121801.161455
Wong LJ, Naviaux RK, Brunetti-Pierri N, Zhang Q, Schmitt ES, Truong C et al (2008) Molecular and clinical genetics of mitochondrial diseases due to POLG mutations. Hum Mutat 29:E150–E172. doi:10.1002/humu.20824
Ropp PA, Copeland WC (1996) Cloning and characterization of the human mitochondrial DNA polymerase, DNA polymerase gamma. Genomics 36:449–458. doi:10.1006/geno.1996.0490
NIEHS—Mitochondrial DNA Replication Group. Human DNA Polymerase Gamma Mutation Database. http://tools.niehs.nih.gov/polg/. Accessed 01 Jul 2016
Milone M, Massie (2010) Polymerase gamma 1 mutations: clinical correlations. Neurologist 16:84–91. doi:10.1097/NRL.0b013e3181c78a89
Colyer MH, Bower KS, Ward TP, Hidayat AA, Subramanian PS (2007) Mitochondrial myopathy presenting with segmental corneal oedema and retrocorneal membrane. Br J Ophthalmol 91:696–697. doi:10.1136/bjo.2006.101055
Blok MJ, van den Bosch BJ, Jongen E, Hendrickx A, de Die-Smulders CE, Hoogendijk JE et al (2009) The unfolding clinical spectrum of POLG mutations. J Med Genet 46:776–785. doi:10.1136/jmg.2009.067686
Chan SS, Copeland WC (2009) DNA polymerase gamma and mitochondrial disease: understanding the consequence of POLG mutations. Biochim Biophys Acta 1787:312–319. doi:10.1016/j.bbabio.2008.10.007
Scuderi C, Borgione E, Castello F, Lo Giudice M, Santa Paola S, Giambirtone M et al (2015) The in cis T251I and P587L POLG1 base changes: description of a new family and literature review. Neuromuscul Disord 25:333–339. doi:10.1016/j.nmd.2015.01.004
Agostino A, Valletta L, Chinnery PF, Ferrari G, Carrara F, Taylor RW et al (2003) Mutations of ANT1, Twinkle and POLG1 in sporadic progressive external ophthalmoplegia (PEO). Neurology 60:1354–1356. doi:10.1212/01.WNL.0000056088.09408.3C
Horvath R, Hudson G, Ferrari G, Fütterer N, Ahola S, Lamantea E et al (2006) Phenotypic spectrum associated with mutations of the mitochondrial polymerase gamma gene. Brain 129:1674–1684. doi:10.1093/brain/awl088
Gago MF, Rosas MJ, Guimarães J, Ferreira M, Vilarinho L, Castro L et al (2006) SANDO: two novel mutations in POLG1 gene. Neuromuscul Disord 16:507–509. doi:10.1016/j.nmd.2006.05.016
Orsucci D, Caldarazzo Ienco E, Mancuso M, Siciliano G (2011) POLG1-related and other “mitochondrial Parkinsonisms”: an overview. J Mol Neurosci 44:17–24. doi:10.1007/s12031-010-9488-9
Schulte C, Synofzik M, Gasser T, Schöls L (2009) Ataxia with ophthalmoplegia or sensory neuropathy is frequently caused by POLG mutations. Neurology 73:898–900. doi:10.1212/WNL.0b013e3181b78488
Burusnukul P, de los Reyes EC (2009) Phenotypic variations in 3 children with POLG1 mutations. J Child Neurol 24:482–486. doi:10.1177/0883073808324539
Hopkins SE, Somoza A, Gilbert DL (2010) Rare autosomal dominant POLG1 mutation in a family with metabolic strokes, posterior column spinal degeneration, and multi-endocrine disease. J Child Neurol 25:752–756. doi:10.1177/0883073809343313
Van Goethem G, Löfgren A, Dermaut B, Ceuterick C, Martin JJ, Van Broeckhoven C (2003) Digenic progressive external ophthalmoplegia in a sporadic patient: recessive mutations in POLG and C10orf2/Twinkle. Hum Mutat 22:175–176. doi:10.1002/humu.10246
Tang S, Wang J, Lee NC, Milone M, Halberg MC, Schmitt ES et al (2011) Mitochondrial DNA polymerase gamma mutations: an ever expanding molecular and clinical spectrum. J Med Genet 48:669–681. doi:10.1136/jmedgenet-2011-100222
Ferreira M, Evangelista T, Almeida LS, Martins J, Macario MC, Martins E et al (2011) Relative frequency of known causes of multiple mtDNA deletions: two novel POLG mutations. Neuromuscul Disord 21:483–488. doi:10.1016/j.nmd.2011.03.011
Kasiviswanathan R, Copeland WC (2011) Biochemical analysis of the G517 V POLG variant reveals wild-type like activity. Mitochondrion 11:929–934. doi:10.1016/j.mito.2011.08.003
Luoma PT, Luo N, Löscher WN, Farr CL, Horvath R, Wanschitz J et al (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. doi:10.1093/hmg/ddi196
Woodbridge P, Liang C, Davis RL, Vandebona H, Sue CM (2013) POLG mutations in Australian patients with mitochondrial disease. Intern Med J 43:150–156. doi:10.1111/j.1445-5994.2012.02847.x
Mancuso M, Filosto M, Oh SJ, DiMauro S (2004) A novel polymerase γ mutation in a family with ophthalmoplegia, neuropathy and parkinsonism. Arch Neurol 61:1777–1779. doi:10.1001/archneur.61.11.1777
Bortot B, Barbi E, Biffi S, Lunazzi G, Busani R, Burlina A et al (2009) Two novel POLG mutations causing hepatic mitochondrial DNA depletion with recurrent hypoketotic hypoglycaemia and fatal liver dysfunction. Dig Liver Dis 41:494–499. doi:10.1016/j.dld.2008.11.013
Acknowledgments
Research was supported in part by a grant from Regione Toscana and Ministry of Public Health to AF (project entitled “Risk and determinants of dementia in patients with mild cognitive impairment and brain subcortical vascular changes: a study of clinical, neuro-imaging and biological markers”).
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Da Pozzo, P., Cardaioli, E., Rubegni, A. et al. Novel POLG mutations and variable clinical phenotypes in 13 Italian patients. Neurol Sci 38, 563–570 (2017). https://doi.org/10.1007/s10072-016-2734-3
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DOI: https://doi.org/10.1007/s10072-016-2734-3