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01-05-2015 | Original Paper

The C9orf72 repeat expansion itself is methylated in ALS and FTLD patients

Authors: Zhengrui Xi, Ming Zhang, Amalia C. Bruni, Raffaele G. Maletta, Rosanna Colao, Pietro Fratta, James M. Polke, Mary G. Sweeney, Ese Mudanohwo, Benedetta Nacmias, Sandro Sorbi, Maria Carmela Tartaglia, Innocenzo Rainero, Elisa Rubino, Lorenzo Pinessi, Daniela Galimberti, Ezequiel I. Surace, Philip McGoldrick, Paul McKeever, Danielle Moreno, Christine Sato, Yan Liang, Julia Keith, Lorne Zinman, Janice Robertson, Ekaterina Rogaeva

Published in: Acta Neuropathologica | Issue 5/2015

Abstract

The most common cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) is a G₄C₂-repeat expansion in C9orf72. However, the lower limit for pathological repeats has not been established and expansions with different sizes could have different pathological consequences. One of the implicated disease mechanisms is haploinsufficiency. Previously, we identified expansion-specific hypermethylation at the 5′ CpG-island near the G₄C₂-repeat, but only in a fraction of carriers (up to 36 %). Here, we tested the hypothesis that the G₄C₂-repeat itself could be the main site of methylation. To evaluate (G₄C₂)_n-methylation, we developed a novel assay, which was validated by an independent methylation-sensitive restriction enzyme assay. Notably, both assays are qualitative but not quantitative. Blood DNA was available for 270 unrelated individuals, including 71 expansion carriers. In addition, we investigated blood DNA from family members of 16 probands, and 38 DNA samples from multiple tissues of 10 expansion carriers. Finally, we tested DNA from different tissues of an ALS patient carrying a somatically unstable 90-repeat. We demonstrated that the G₄C₂-expansion is generally methylated in unrelated carriers of alleles >50 repeats (97 %), while small (<22 repeats) or intermediate (22–90 repeats) alleles were completely unmethylated. The presence of (G₄C₂)_n-methylation does not separate the C9orf72-phenotypes (ALS vs. ALS/FTLD vs. FTLD), but has the potential to predict large vs. intermediate repeat length. Our results suggest that (G₄C₂)_n-methylation might sometimes spread to the 5′-upstream region, but not vice versa. It is stable over time, since (G₄C₂)_n-methylation was detected in carriers with a wide range of ages (24–74 years). It was identified in both blood and brain tissues for the same individual, implying its potential use as a biomarker. Furthermore, our findings may open up new perspectives for studying disease mechanisms, such as determining whether methylated and unmethylated repeats have the same ability to form a G-quadruplex configuration.

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Al-Mahdawi S, Pinto RM, Ismail O, Varshney D, Lymperi S, Sandi C, Trabzuni D, Pook M (2008) The Friedreich ataxia GAA repeat expansion mutation induces comparable epigenetic changes in human and transgenic mouse brain and heart tissues. Hum Mol Genet 17:735–746. doi:10.1093/hmg/ddm346 CrossRefPubMed

Ash PE, Bieniek KF, Gendron TF, Caulfield T, Lin WL, Dejesus-Hernandez M, van Blitterswijk MM, Jansen-West K, Paul JW 3rd, Rademakers R, Boylan KB, Dickson DW, Petrucelli L (2013) Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS. Neuron 77:639–646. doi:10.1016/j.neuron.2013.02.004 CrossRefPubMedCentralPubMed

Bell MV, Hirst MC, Nakahori Y, MacKinnon RN, Roche A, Flint TJ, Jacobs PA, Tommerup N, Tranebjaerg L, Froster-Iskenius U et al (1991) Physical mapping across the fragile X: hypermethylation and clinical expression of the fragile X syndrome. Cell 64:861–866CrossRefPubMed

Belzil VV, Bauer PO, Gendron TF, Murray ME, Dickson D, Petrucelli L (2014) Characterization of DNA hypermethylation in the cerebellum of c9FTD/ALS patients. Brain Res 1584:15–21. doi:10.1016/j.brainres.2014.02.015 CrossRefPubMed

Brooks BR, Miller RG, Swash M, Munsat TL (2000) El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord 1:293–299CrossRefPubMed

Ciura S, Lattante S, Le Ber I, Latouche M, Tostivint H, Brice A, Kabashi E (2013) Loss of function of C9orf72 causes motor deficits in a zebrafish model of Amyotrophic Lateral Sclerosis. Ann Neurol 74:180–187. doi:10.1002/ana.23946 PubMed

(1994) Clinical and neuropathological criteria for frontotemporal dementia. The Lund and Manchester Groups. J Neurol Neurosurg Psychiatry 57:416–418

Cooper-Knock J, Higginbottom A, Connor-Robson N, Bayatti N, Bury JJ, Kirby J, Ninkina N, Buchman VL, Shaw PJ (2013) C9ORF72 transcription in a frontotemporal dementia case with two expanded alleles. Neurology 81:1719–1721. doi:10.1212/01.wnl.0000435295.41974.2e CrossRefPubMedCentralPubMed

Davidson YS, Barker H, Robinson AC, Thompson JC, Harris J, Troakes C, Smith B, Al-Saraj S, Shaw C, Rollinson S, Masuda-Suzukake M, Hasegawa M, Pickering-Brown S, Snowden JS, Mann DM (2014) Brain distribution of dipeptide repeat proteins in frontotemporal lobar degeneration and motor neurone disease associated with expansions in C9ORF72. Acta Neuropathol Commun 2:70. doi:10.1186/2051-5960-2-70 CrossRefPubMedCentralPubMed

10.

De S, Michor F (2011) DNA secondary structures and epigenetic determinants of cancer genome evolution. Nat Struct Mol Biol 18:950–955. doi:10.1038/nsmb.2089 CrossRefPubMedCentralPubMed

11.

DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ, Nicholson AM, Finch NA, Flynn H, Adamson J, Kouri N, Wojtas A, Sengdy P, Hsiung GY, Karydas A, Seeley WW, Josephs KA, Coppola G, Geschwind DH, Wszolek ZK, Feldman H, Knopman DS, Petersen RC, Miller BL, Dickson DW, Boylan KB, Graff-Radford NR, Rademakers R (2011) Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72:245–256. doi:10.1016/j.neuron.2011.09.011 CrossRefPubMedCentralPubMed

12.

Donnelly CJ, Zhang PW, Pham JT, Haeusler AR, Mistry NA, Vidensky S, Daley EL, Poth EM, Hoover B, Fines DM, Maragakis N, Tienari PJ, Petrucelli L, Traynor BJ, Wang J, Rigo F, Bennett CF, Blackshaw S, Sattler R, Rothstein JD (2013) RNA toxicity from the ALS/FTD C9ORF72 expansion is mitigated by antisense intervention. Neuron 80:415–428. doi:10.1016/j.neuron.2013.10.015 CrossRefPubMedCentralPubMed

13.

Evans-Galea MV, Carrodus N, Rowley SM, Corben LA, Tai G, Saffery R, Galati JC, Wong NC, Craig JM, Lynch DR, Regner SR, Brocht AF, Perlman SL, Bushara KO, Gomez CM, Wilmot GR, Li L, Varley E, Delatycki MB, Sarsero JP (2012) FXN methylation predicts expression and clinical outcome in Friedreich ataxia. Ann Neurol 71:487–497. doi:10.1002/ana.22671 CrossRefPubMed

14.

Fratta P, Mizielinska S, Nicoll AJ, Zloh M, Fisher EM, Parkinson G, Isaacs AM (2012) C9orf72 hexanucleotide repeat associated with amyotrophic lateral sclerosis and frontotemporal dementia forms RNA G-quadruplexes. Sci Rep 2:1016. doi:10.1038/srep01016 CrossRefPubMedCentralPubMed

15.

Fratta P, Polke JM, Newcombe J, Mizielinska S, Lashley T, Poulter M, Beck J, Preza E, Devoy A, Sidle K, Howard R, Malaspina A, Orrell RW, Clarke J, Lu CH, Mok K, Collins T, Shoaii M, Nanji T, Wray S, Adamson G, Pittman A, Renton AE, Traynor BJ, Sweeney MG, Revesz T, Houlden H, Mead S, Isaacs AM, Fisher EM (2014) Screening a UK amyotrophic lateral sclerosis cohort provides evidence of multiple origins of the C9orf72 expansion. Neurobiol Aging 36(546):e541–e547. doi:10.1016/j.neurobiolaging.2014.07.037

16.

Fratta P, Poulter M, Lashley T, Rohrer JD, Polke JM, Beck J, Ryan N, Hensman D, Mizielinska S, Waite AJ, Lai MC, Gendron TF, Petrucelli L, Fisher EM, Revesz T, Warren JD, Collinge J, Isaacs AM, Mead S (2013) Homozygosity for the C9orf72 GGGGCC repeat expansion in frontotemporal dementia. Acta Neuropathol 126:401–409. doi:10.1007/s00401-013-1147-0 CrossRefPubMedCentralPubMed

17.

Gendron TF, Bieniek KF, Zhang YJ, Jansen-West K, Ash PE, Caulfield T, Daughrity L, Dunmore JH, Castanedes-Casey M, Chew J, Cosio DM, van Blitterswijk M, Lee WC, Rademakers R, Boylan KB, Dickson DW, Petrucelli L (2013) Antisense transcripts of the expanded C9ORF72 hexanucleotide repeat form nuclear RNA foci and undergo repeat-associated non-ATG translation in c9FTD/ALS. Acta Neuropathol 126:829–844. doi:10.1007/s00401-013-1192-8 CrossRefPubMedCentralPubMed

18.

Gijselinck I, Van Langenhove T, van der Zee J, Sleegers K, Philtjens S, Kleinberger G, Janssens J, Bettens K, Van Cauwenberghe C, Pereson S, Engelborghs S, Sieben A, De Jonghe P, Vandenberghe R, Santens P, De Bleecker J, Maes G, Baumer V, Dillen L, Joris G, Cuijt I, Corsmit E, Elinck E, Van Dongen J, Vermeulen S, Van den Broeck M, Vaerenberg C, Mattheijssens M, Peeters K, Robberecht W, Cras P, Martin JJ, De Deyn PP, Cruts M, Van Broeckhoven C (2012) A C9orf72 promoter repeat expansion in a Flanders-Belgian cohort with disorders of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum: a gene identification study. Lancet Neurol 11:54–65. doi:10.1016/S1474-4422(11)70261-7 CrossRefPubMed

19.

Greene E, Mahishi L, Entezam A, Kumari D, Usdin K (2007) Repeat-induced epigenetic changes in intron 1 of the frataxin gene and its consequences in Friedreich ataxia. Nucleic Acids Res 35:3383–3390. doi:10.1093/nar/gkm271 CrossRefPubMedCentralPubMed

20.

Haeusler AR, Donnelly CJ, Periz G, Simko EA, Shaw PG, Kim MS, Maragakis NJ, Troncoso JC, Pandey A, Sattler R, Rothstein JD, Wang J (2014) C9orf72 nucleotide repeat structures initiate molecular cascades of disease. Nature 507:195–200. doi:10.1038/nature13124 CrossRefPubMedCentralPubMed

21.

Halder R, Halder K, Sharma P, Garg G, Sengupta S, Chowdhury S (2010) Guanine quadruplex DNA structure restricts methylation of CpG dinucleotides genome-wide. Mol BioSyst 6:2439–2447. doi:10.1039/c0mb00009d CrossRefPubMed

22.

Hardy J, Rogaeva E (2013) Motor neuron disease and frontotemporal dementia: sometimes related, sometimes not. Exp Neurol 262 Pt B:75–83. doi:10.1016/j.expneurol.2013.11.006

23.

Herman JG, Graff JR, Myohanen S, Nelkin BD, Baylin SB (1996) Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci USA 93:9821–9826CrossRefPubMedCentralPubMed

24.

Hughes AJ, Daniel SE, Lees AJ (2001) Improved accuracy of clinical diagnosis of Lewy body Parkinson’s disease. Neurology 57:1497–1499CrossRefPubMed

25.

Jones PA, Takai D (2001) The role of DNA methylation in mammalian epigenetics. Science 293:1068–1070. doi:10.1126/science.1063852 CrossRefPubMed

26.

Klesert TR, Otten AD, Bird TD, Tapscott SJ (1997) Trinucleotide repeat expansion at the myotonic dystrophy locus reduces expression of DMAHP. Nat Genet 16:402–406. doi:10.1038/ng0897-402 CrossRefPubMed

27.

Korade-Mirnics Z, Tarleton J, Servidei S, Casey RR, Gennarelli M, Pegoraro E, Angelini C, Hoffman EP (1999) Myotonic dystrophy: tissue-specific effect of somatic CTG expansions on allele-specific DMAHP/SIX5 expression. Hum Mol Genet 8:1017–1023CrossRefPubMed

28.

Lagier-Tourenne C, Baughn M, Rigo F, Sun S, Liu P, Li HR, Jiang J, Watt AT, Chun S, Katz M, Qiu J, Sun Y, Ling SC, Zhu Q, Polymenidou M, Drenner K, Artates JW, McAlonis-Downes M, Markmiller S, Hutt KR, Pizzo DP, Cady J, Harms MB, Baloh RH, Vandenberg SR, Yeo GW, Fu XD, Bennett CF, Cleveland DW, Ravits J (2013) Targeted degradation of sense and antisense C9orf72 RNA foci as therapy for ALS and frontotemporal degeneration. Proc Natl Acad Sci USA 110:E4530–E4539. doi:10.1073/pnas.1318835110 CrossRefPubMedCentralPubMed

29.

Li LC, Dahiya R (2002) MethPrimer: designing primers for methylation PCRs. Bioinformatics 18:1427–1431CrossRefPubMed

30.

Liu EY, Russ J, Wu K, Neal D, Suh E, McNally AG, Irwin DJ, Van Deerlin VM, Lee EB (2014) C9orf72 hypermethylation protects against repeat expansion-associated pathology in ALS/FTD. Acta Neuropathol 128:525–541. doi:10.1007/s00401-014-1286-y CrossRefPubMed

31.

Maizels N, Gray LT (2013) The G4 genome. PLoS Genet 9:e1003468. doi:10.1371/journal.pgen.1003468 CrossRefPubMedCentralPubMed

32.

Mann DM, Rollinson S, Robinson A, Bennion Callister J, Thompson JC, Snowden JS, Gendron T, Petrucelli L, Masuda-Suzukake M, Hasegawa M, Davidson Y, Pickering-Brown S (2013) Dipeptide repeat proteins are present in the p62 positive inclusions in patients with frontotemporal lobar degeneration and motor neurone disease associated with expansions in C9ORF72. Acta Neuropathol Commun 1:68. doi:10.1186/2051-5960-1-68 CrossRefPubMedCentralPubMed

33.

Mizielinska S, Lashley T, Norona FE, Clayton EL, Ridler CE, Fratta P, Isaacs AM (2013) C9orf72 frontotemporal lobar degeneration is characterised by frequent neuronal sense and antisense RNA foci. Acta Neuropathol 126:845–857. doi:10.1007/s00401-013-1200-z CrossRefPubMedCentralPubMed

34.

Mori K, Arzberger T, Grasser FA, Gijselinck I, May S, Rentzsch K, Weng SM, Schludi MH, van der Zee J, Cruts M, Van Broeckhoven C, Kremmer E, Kretzschmar HA, Haass C, Edbauer D (2013) Bidirectional transcripts of the expanded C9orf72 hexanucleotide repeat are translated into aggregating dipeptide repeat proteins. Acta Neuropathol 126:881–893. doi:10.1007/s00401-013-1189-3 CrossRefPubMed

35.

Mori K, Weng SM, Arzberger T, May S, Rentzsch K, Kremmer E, Schmid B, Kretzschmar HA, Cruts M, Van Broeckhoven C, Haass C, Edbauer D (2013) The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS. Science 339:1335–1338. doi:10.1126/science.1232927 CrossRefPubMed

36.

Naumann A, Hochstein N, Weber S, Fanning E, Doerfler W (2009) A distinct DNA-methylation boundary in the 5′-upstream sequence of the FMR1 promoter binds nuclear proteins and is lost in fragile X syndrome. Am J Hum Genet 85:606–616. doi:10.1016/j.ajhg.2009.09.018 CrossRefPubMedCentralPubMed

37.

Pieretti M, Zhang FP, Fu YH, Warren ST, Oostra BA, Caskey CT, Nelson DL (1991) Absence of expression of the FMR-1 gene in fragile X syndrome. Cell 66:817–822CrossRefPubMed

38.

Proudfoot M, Gutowski NJ, Edbauer D, Hilton DA, Stephens M, Rankin J, Mackenzie IR (2014) Early dipeptide repeat pathology in a frontotemporal dementia kindred with C9ORF72 mutation and intellectual disability. Acta Neuropathol 127:451–458. doi:10.1007/s00401-014-1245-7 CrossRefPubMed

39.

Rademakers R (2012) C9orf72 repeat expansions in patients with ALS and FTD. Lancet Neurol 11:297–298. doi:10.1016/S1474-4422(12)70046-7 CrossRefPubMedCentralPubMed

40.

Reddy K, Zamiri B, Stanley SY, Macgregor RB Jr, Pearson CE (2013) The disease-associated r(GGGGCC)n repeat from the C9orf72 gene forms tract length-dependent uni- and multimolecular RNA G-quadruplex structures. J Biol Chem 288:9860–9866. doi:10.1074/jbc.C113.452532 CrossRefPubMedCentralPubMed

41.

Renton AE, Majounie E, Waite A, Simon-Sanchez J, Rollinson S, Gibbs JR, Schymick JC, Laaksovirta H, van Swieten JC, Myllykangas L, Kalimo H, Paetau A, Abramzon Y, Remes AM, Kaganovich A, Scholz SW, Duckworth J, Ding J, Harmer DW, Hernandez DG, Johnson JO, Mok K, Ryten M, Trabzuni D, Guerreiro RJ, Orrell RW, Neal J, Murray A, Pearson J, Jansen IE, Sondervan D, Seelaar H, Blake D, Young K, Halliwell N, Callister JB, Toulson G, Richardson A, Gerhard A, Snowden J, Mann D, Neary D, Nalls MA, Peuralinna T, Jansson L, Isoviita VM, Kaivorinne AL, Holtta-Vuori M, Ikonen E, Sulkava R, Benatar M, Wuu J, Chio A, Restagno G, Borghero G, Sabatelli M, Heckerman D, Rogaeva E, Zinman L, Rothstein JD, Sendtner M, Drepper C, Eichler EE, Alkan C, Abdullaev Z, Pack SD, Dutra A, Pak E, Hardy J, Singleton A, Williams NM, Heutink P, Pickering-Brown S, Morris HR, Tienari PJ, Traynor BJ (2011) A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72:257–268. doi:10.1016/j.neuron.2011.09.010 CrossRefPubMedCentralPubMed

42.

Russ J, Liu EY, Wu K, Neal D, Suh E, Irwin DJ, McMillan CT, Harms MB, Cairns NJ, Wood EM, Xie SX, Elman L, McCluskey L, Grossman M, Van Deerlin VM, Lee EB (2014) Hypermethylation of repeat expanded C9orf72 is a clinical and molecular disease modifier. Acta Neuropathol 129:39–52. doi:10.1007/s00401-014-1365-0 CrossRefPubMedCentralPubMed

43.

Sutcliffe JS, Nelson DL, Zhang F, Pieretti M, Caskey CT, Saxe D, Warren ST (1992) DNA methylation represses FMR-1 transcription in fragile X syndrome. Hum Mol Genet 1:397–400CrossRefPubMed

44.

Therrien M, Rouleau GA, Dion PA, Parker JA (2013) Deletion of C9ORF72 results in motor neuron degeneration and stress sensitivity in C. elegans. PLoS One 8:e83450. doi:10.1371/journal.pone.0083450 CrossRefPubMedCentralPubMed

45.

Thornton CA, Wymer JP, Simmons Z, McClain C, Moxley RT 3rd (1997) Expansion of the myotonic dystrophy CTG repeat reduces expression of the flanking DMAHP gene. Nat Genet 16:407–409. doi:10.1038/ng0897-407 CrossRefPubMed

46.

Van Langenhove T, van der Zee J, Van Broeckhoven C (2012) The molecular basis of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum. Ann Med 44:817–828. doi:10.3109/07853890.2012.665471 CrossRefPubMedCentralPubMed

47.

Waite AJ, Baumer D, East S, Neal J, Morris HR, Ansorge O, Blake DJ (2014) Reduced C9orf72 protein levels in frontal cortex of amyotrophic lateral sclerosis and frontotemporal degeneration brain with the C9ORF72 hexanucleotide repeat expansion. Neurobiol Aging 35:1779 e1775–1779 e1713. doi:10.1016/j.neurobiolaging.2014.01.016

48.

Warner JP, Barron LH, Goudie D, Kelly K, Dow D, Fitzpatrick DR, Brock DJ (1996) A general method for the detection of large CAG repeat expansions by fluorescent PCR. J Med Genet 33:1022–1026CrossRefPubMedCentralPubMed

49.

Xi Z, Rainero I, Rubino E, Pinessi L, Bruni AC, Maletta RG, Nacmias B, Sorbi S, Galimberti D, Surace EI, Zheng Y, Moreno D, Sato C, Liang Y, Zhou Y, Robertson J, Zinman L, Tartaglia MC, St George-Hyslop P, Rogaeva E (2014) Hypermethylation of the CpG-island near the C9orf72 G(4)C(2)-repeat expansion in FTLD patients. Hum Mol Genet 23:5630–5637. doi:10.1093/hmg/ddu279 CrossRefPubMed

50.

Xi Z, Yunusova Y, van Blitterswijk M, Dib S, Ghani M, Moreno D, Sato C, Liang Y, Singleton A, Robertson J, Rademakers R, Zinman L, Rogaeva E (2014) Identical twins with the C9orf72 repeat expansion are discordant for ALS. Neurology 83:1476–1478. doi:10.1212/WNL.0000000000000886 CrossRefPubMed

51.

Xi Z, Zinman L, Grinberg Y, Moreno D, Sato C, Bilbao JM, Ghani M, Hernandez I, Ruiz A, Boada M, Moron FJ, Lang AE, Marras C, Bruni A, Colao R, Maletta RG, Puccio G, Rainero I, Pinessi L, Galimberti D, Morrison KE, Moorby C, Stockton JD, Masellis M, Black SE, Hazrati LN, Liang Y, van Haersma de With J, Fornazzari L, Villagra R, Rojas-Garcia R, Clarimon J, Mayeux R, Robertson J, StGeorge-Hyslop P, Rogaeva E (2012) Investigation of c9orf72 in 4 neurodegenerative disorders. Arch Neurol 69:1583–1590. doi:10.1001/archneurol.2012.2016 CrossRefPubMedCentralPubMed

52.

Xi Z, Zinman L, Moreno D, Schymick J, Liang Y, Sato C, Zheng Y, Ghani M, Dib S, Keith J, Robertson J, Rogaeva E (2013) Hypermethylation of the CpG Island near the GC repeat in ALS with a C9orf72 expansion. Am J Hum Genet 92:981–989. doi:10.1016/j.ajhg.2013.04.017 CrossRefPubMedCentralPubMed

53.

Zhou Y, Lum JM, Yeo GH, Kiing J, Tay SK, Chong SS (2006) Simplified molecular diagnosis of fragile X syndrome by fluorescent methylation-specific PCR and GeneScan analysis. Clin Chem 52:1492–1500. doi:10.1373/clinchem.2006.068593 CrossRefPubMed

54.

Zu T, Liu Y, Banez-Coronel M, Reid T, Pletnikova O, Lewis J, Miller TM, Harms MB, Falchook AE, Subramony SH, Ostrow LW, Rothstein JD, Troncoso JC, Ranum LP (2013) RAN proteins and RNA foci from antisense transcripts in C9ORF72 ALS and frontotemporal dementia. Proc Natl Acad Sci USA 110:E4968–E4977. doi:10.1073/pnas.1315438110 CrossRefPubMedCentralPubMed

Title: The C9orf72 repeat expansion itself is methylated in ALS and FTLD patients
Authors: Zhengrui Xi
Ming Zhang
Amalia C. Bruni
Raffaele G. Maletta
Rosanna Colao
Pietro Fratta
James M. Polke
Mary G. Sweeney
Ese Mudanohwo
Benedetta Nacmias
Sandro Sorbi
Maria Carmela Tartaglia
Innocenzo Rainero
Elisa Rubino
Lorenzo Pinessi
Daniela Galimberti
Ezequiel I. Surace
Philip McGoldrick
Paul McKeever
Danielle Moreno
Christine Sato
Yan Liang
Julia Keith
Lorne Zinman
Janice Robertson
Ekaterina Rogaeva
Publication date: 01-05-2015
Publisher: Springer Berlin Heidelberg
Published in: Acta Neuropathologica / Issue 5/2015
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-015-1401-8

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The C9orf72 repeat expansion itself is methylated in ALS and FTLD patients

Abstract

Keynote webinar | Spotlight on medication adherence

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Abstract

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Acknowledgement to referees