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BMC Neurology
Published in: BMC Neurology 1/2010

Open Access 01-12-2010 | Research article

POLG1 p.R722H mutation associated with multiple mtDNA deletions and a neurological phenotype

Authors: Tuomas Komulainen, Reetta Hinttala, Mikko Kärppä, Leila Pajunen, Saara Finnilä, Hannu Tuominen, Heikki Rantala, Ilmo Hassinen, Kari Majamaa, Johanna Uusimaa

Published in: BMC Neurology | Issue 1/2010

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Abstract

Background

The c.2447G>A (p.R722H) mutation in the gene POLG1 of the catalytic subunit of human mitochondrial polymerase gamma has been previously found in a few occasions but its pathogenicity has remained uncertain. We set out to ascertain its contribution to neuromuscular disease.

Methods

Probands from two families with probable mitochondrial disease were examined clinically, muscle and buccal epithelial DNA were analyzed for mtDNA deletions, and the POLG1, POLG2, ANT1 and Twinkle genes were sequenced.

Results

An adult proband presented with progressive external ophthalmoplegia, sensorineural hearing impairment, diabetes mellitus, dysphagia, a limb myopathy and dementia. Brain MRI showed central and cortical atrophy, and 18F-deoxyglucose PET revealed reduced glucose uptake. Histochemical analysis of muscle disclosed ragged red fibers and cytochrome c oxidase-negative fibers. Electron microscopy showed subsarcolemmal aggregates of morphologically normal mitochondria. Multiple mtDNA deletions were found in the muscle, and sequencing of the POLG1 gene revealed a homozygous c.2447G>A (p.R722H) mutation. His two siblings were also homozygous with respect to the p.R722H mutation and presented with dementia and sensorineural hearing impairment. In another family the p.R722H mutation was found as compound heterozygosity with the common p.W748S mutation in two siblings with mental retardation, ptosis, epilepsy and psychiatric symptoms. The estimated carrier frequency of the p.R722H mutation was 1:135 in the Finnish population. No mutations in POLG2, ANT1 and Twinkle genes were found. Analysis of the POLG1 sequence by homology modeling supported the notion that the p.R722H mutation is pathogenic.

Conclusions

The recessive c.2447G>A (p.R722H) mutation in the linker region of the POLG1 gene is pathogenic for multiple mtDNA deletions in muscle and is associated with a late-onset neurological phenotype as a homozygous state. The onset of the disease can be earlier in compound heterozygotes.
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Literature
1.
Graziewicz MA, Longley MJ, Copeland WC: DNA polymarase γ in mitochondrial DNA replication and repair. Chem Rev. 2006, 106: 383-405. 10.1021/cr040463d.CrossRefPubMed
2.
Kaguni LS: DNA polymerase γ, the mitochondrial replicase. Annu Rev Biochem. 2004, 73: 290-320. 10.1146/annurev.biochem.72.121801.161455.CrossRef
3.
Hudson G, Chinnery PF: Mitochondrial DNA polymerase-γ and human disease. Hum Mol Genet. 2006, 15: 244-255. 10.1093/hmg/ddl233.CrossRef
4.
Yakubovskaya E, Lukin M, Chen Z, Berriman J, Wall JS, Kobayashi R, Kisker C, Bogenhagen DF: The EM structure of human DNA polymerase γ reveals a localized contact between the catalytic and accessory subunits. EMBO J. 2007, 26: 4283-4291. 10.1038/sj.emboj.7601843.CrossRefPubMedPubMedCentral
5.
Horvath R, Hudson G, Ferrari G, Fütterer N, Ahola S, Lamantea E, Prokisch H, Lochmüller 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 γ gene. Brain. 2006, 129: 1674-1684. 10.1093/brain/awl088.CrossRefPubMed
6.
Longley MJ, Graziewicz MA, Bienstock RJ, Copeland WC: Consequences of mutations in mitochondrial DNA polymerase γ. Gene. 2005, 354: 125-131. 10.1016/j.gene.2005.03.029.CrossRefPubMed
7.
Van Goethem G, Dermaut B, Löfgren A, Martin JJ, Van Broechoven C: Mutation of POLG is associated with progressive external ophthalmoplegia characterized by mtDNA deletions. Nat Genet. 2001, 28: 211-212. 10.1038/90034.CrossRefPubMed
8.
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 γA are a requent cause of autosomal dominant or recessive progressive external ophtaloplegia. Ann Neurol. 2002, 52: 211-219. 10.1002/ana.10278.CrossRefPubMed
9.
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, 60: 1354-1356.CrossRefPubMed
10.
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 heterogenity in progressive external ophthalmoplegia due to mutations in polymerase γ. Arch Neurol. 2003, 60: 1279-1284. 10.1001/archneur.60.9.1279.CrossRefPubMed
11.
Van Goethem G, Martin JJ, Dermaut B, Löfgren 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 compund heterozygote patients with progressive external ophthalmoplegia. Neuromuscul Disord. 2003, 13: 133-142. 10.1016/S0960-8966(02)00216-X.CrossRefPubMed
12.
Van Goethem G, Luoma P, Rantamäki M, Al Memar A, Kaakkola S, Hackman P, Krahe R, Löfgren 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, 63: 1251-1257.CrossRefPubMed
13.
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, 64: 1204-1208.CrossRefPubMed
14.
Luoma PT, Eerola J, Ahola S, Hakonen AH, Hellström O, Kivistö KT, Tienari PJ, Suomalainen A: Mitochondrial DNA polymerase gamma variants in idiopathic sporadic Parkinson disease. Neurology. 2007, 69: 1152-1159. 10.1212/01.wnl.0000276955.23735.eb.CrossRefPubMed
15.
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 γ mutations: clinical and molecular genetic study. Lancet. 2004, 364: 875-882. 10.1016/S0140-6736(04)16983-3.CrossRefPubMed
16.
Naviaux RK, Nguyen KV: POLG mutations associated with Alpers' syndrome and mitochondrial DNA depletion. Ann Neurol. 2004, 55: 706-712. 10.1002/ana.20079.CrossRefPubMed
17.
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-γA. Brain. 2005, 128: 723-731. 10.1093/brain/awh410.CrossRefPubMed
18.
Tzoulis C, Engelsen BA, Telstad W, Aasly J, Zeviani M, Winterthun S, Ferrari G, Aarseth JH, Bindoff LA: The spectrum of clinical disease caused by the A467T and W748S POLG mutations: a study of 26 cases. Brain. 2006, 129: 1685-1692. 10.1093/brain/awl097.CrossRefPubMed
19.
Uusimaa J, Hinttala R, Rantala H, Päivärinta M, Herva R, Röyttä M, Soini H, Moilanen JS, Remes AM, Hassinen IE, Majamaa K: Homozygous W748S mutation in the POLG1 gene in patients with juvenile-onset Alpers' syndrome and status epilepticus. Epilepsia. 2008, 49: 1038-1045. 10.1111/j.1528-1167.2008.01544.x.CrossRefPubMed
20.
21.
González-Vioque E, Blázquez A, Fernández-Moreira D, Bornstein B, Bautista J, Arpa J, Navarro C, Campos Y, Fernández-Moreno MA, Garesse R, Arenas J, Martín MA: Association of novel POLG mutations and multiple mitochondrial DNA deletions with variable clinical phenotypes in Spanish population. Arch Neurol. 2006, 63: 107-111. 10.1001/archneur.63.1.107.CrossRefPubMed
22.
Copeland WC: Inherited mitochondrial diseases of DNA replication. Annu Rev Med. 2008, 59: 309-324. 10.1146/annurev.med.59.053006.104646.CrossRef
23.
Van Goethem G, Martin JJ, Van Broeckhoven C: Progressive external ophtalmoplegia and multiple mitochondrial deletions. Acta Neurol Belg. 2002, 102: 39-42.PubMed
24.
Remes AM, Majamaa-Voltti K, Kärppä M, Moilanen JS, Uimonen S, Helander H, Rusanen H, Salmela PI, Sorri M, Hassinen IE, Majamaa K: Prevalence of large scale mitochodrial DNA deletions in an adult Finnish population. Neurology. 2005, 64: 976-981.CrossRefPubMed
25.
Cole C, Barber JD, Barton GJ: The Jpred 3 secondary structure prediction server. Nucleic Acids Research. 2008, 36 (Suppl 2): 197-201. 10.1093/nar/gkn238.CrossRef
26.
Sali A, Blundell TL: Comparative protein modelling by satisfaction of spatial restraints. J Mol Biol. 1993, 234: 779-815. 10.1006/jmbi.1993.1626.CrossRefPubMed
27.
Koradi R, Billeter M, Wuthrich K: MOLMOL: A program for display and analysis of macromolecular structures. J Mol Graph. 1996, 14: 51-55. 10.1016/0263-7855(96)00009-4. 29-32CrossRefPubMed
28.
Braasch DA, Corey DR: Locked nucleic acid (LNA): fine-tuning the recognition of DNA and RNA. Chem Biol. 2001, 8: 1-7. 10.1016/S1074-5521(00)00058-2.CrossRefPubMed
29.
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, 77: 430-441. 10.1086/444548.CrossRefPubMedPubMedCentral
30.
Hopkins SE, Somoza A, Gilbert DL: Rare autosomal dominant POLG1 mutation in a family with metabolic strokes, posterior column spinal degeneration, and multi-endocrine disease. J Child Neurol. 2009
31.
Luoma PT, Luo N, Löscher 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, 14: 1907-1920. 10.1093/hmg/ddi196.CrossRefPubMed
32.
Chan SSL, Longley MJ, Copeland WC: The common A467T mutation in the human mitochondrial DNA polymerase (POLG) compromises catalytic efficiency and interaction with the accessory subunit. J Biol Chem. 2005, 280: 31341-31346. 10.1074/jbc.M506762200.CrossRefPubMed
33.
Chan SSL, Longley MJ, Copeland WC: Modulation of the W748S mutation in DNA polymerase γ by the E1143G polymorphism in mitochondrial disorders. Hum Mol Genet. 2006, 15: 3473-3483. 10.1093/hmg/ddl424.CrossRefPubMedPubMedCentral
34.
Beese LS, Derbyshire V, Steitz TA: Structure of DNA polymerase I Klenow fragment bound to duplex DNA. Science. 1993, 260: 352-355. 10.1126/science.8469987.CrossRefPubMed
35.
Minnick DT, Bebenek K, Osheroff WP, Turner RM, Astatke M, Liu L, Kunkel TA, Joyce CM: Side chains that influence fidelity at the polymerase active site of Escherichia coli DNA polymerase I (Klenow fragment). J Biol Chem. 1999, 274: 3067-3075. 10.1074/jbc.274.5.3067.CrossRefPubMed
36.
Luo N, Kaguni LS: Mutations in the spacer region of Drosophila mitochondrial DNA polymerase affect DNA binding, processivity, and the balance between Pol and Exo function. J Biol Chem. 2005, 280: 2491-2497. 10.1074/jbc.M411447200.CrossRefPubMed
37.
Kollberg G, Moslemi AR, Darin N, Nennesmo I, Bjarnadottir I, Uvebrant P, Holme E, Melberg A, Tulinius M, Oldfors A: POLG1 mutations associated with progressive encephalopathy in childhood. J Neuropathol Exp Neurol. 2006, 65: 758-768. 10.1097/01.jnen.0000229987.17548.6e.CrossRefPubMed
Metadata
Title
POLG1 p.R722H mutation associated with multiple mtDNA deletions and a neurological phenotype
Authors
Tuomas Komulainen
Reetta Hinttala
Mikko Kärppä
Leila Pajunen
Saara Finnilä
Hannu Tuominen
Heikki Rantala
Ilmo Hassinen
Kari Majamaa
Johanna Uusimaa
Publication date
01-12-2010
Publisher
BioMed Central
Published in
BMC Neurology / Issue 1/2010
Electronic ISSN: 1471-2377
DOI
https://doi.org/10.1186/1471-2377-10-29

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