Acta Neuropathologica

, Volume 128, Issue 4, pp 525–541 | Cite as

C9orf72 hypermethylation protects against repeat expansion-associated pathology in ALS/FTD

  • Elaine Y. Liu
  • Jenny Russ
  • Kathryn Wu
  • Donald Neal
  • Eunran Suh
  • Anna G. McNally
  • David J. Irwin
  • Vivianna M. Van Deerlin
  • Edward B. Lee
Original Paper

Abstract

Hexanucleotide repeat expansions of C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal degeneration. The mutation is associated with reduced C9orf72 expression and the accumulation of potentially toxic RNA and protein aggregates. CpG methylation is known to protect the genome against unstable DNA elements and to stably silence inappropriate gene expression. Using bisulfite cloning and restriction enzyme-based methylation assays on DNA from human brain and peripheral blood, we observed CpG hypermethylation involving the C9orf72 promoter in cis to the repeat expansion mutation in approximately one-third of C9orf72 repeat expansion mutation carriers. Promoter hypermethylation of mutant C9orf72 was associated with transcriptional silencing of C9orf72 in patient-derived lymphoblast cell lines, resulting in reduced accumulation of intronic C9orf72 RNA and reduced numbers of RNA foci. Furthermore, demethylation of mutant C9orf72 with 5-aza-deoxycytidine resulted in increased vulnerability of mutant cells to oxidative and autophagic stress. Promoter hypermethylation of repeat expansion carriers was also associated with reduced accumulation of RNA foci and dipeptide repeat protein aggregates in human brains. These results indicate that C9orf72 promoter hypermethylation prevents downstream molecular aberrations associated with the hexanucleotide repeat expansion, suggesting that epigenetic silencing of the mutant C9orf72 allele may represent a protective counter-regulatory response to hexanucleotide repeat expansion.

Keywords

Neurodegeneration Amyotrophic lateral sclerosis Dementia Motor neuron disease Frontotemporal lobar degeneration Epigenetics 

Supplementary material

401_2014_1286_MOESM1_ESM.pdf (399 kb)
Supplementary material 1 (PDF 399 kb)

References

  1. 1.
    Almeida S, Gascon E, Tran H, Chou HJ, Gendron TF, Degroot S, Tapper AR, Sellier C, Charlet-Berguerand N, Karydas A, Seeley WW, Boxer AL, Petrucelli L, Miller BL, Gao FB (2013) Modeling key pathological features of frontotemporal dementia with C9ORF72 repeat expansion in iPSC-derived human neurons. Acta Neuropathol 126(3):385–399. doi:10.1007/s00401-013-1149-y PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    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(4):639–646. doi:10.1016/j.neuron.2013.02.004 PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Belzil VV, Bauer PO, Prudencio M, Gendron TF, Stetler CT, Yan IK, Pregent L, Daughrity L, Baker MC, Rademakers R, Boylan K, Patel TC, Dickson DW, Petrucelli L (2013) Reduced C9orf72 gene expression in c9FTD/ALS is caused by histone trimethylation, an epigenetic event detectable in blood. Acta Neuropathol 126(6):895–905. doi:10.1007/s00401-013-1199-1 PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Benussi L, Rossi G, Glionna M, Tonoli E, Piccoli E, Fostinelli S, Paterlini A, Flocco R, Albani D, Pantieri R, Cereda C, Forloni G, Tagliavini F, Binetti G, Ghidoni R (2013) C9ORF72 hexanucleotide repeat number in frontotemporal lobar degeneration: a genotype–phenotype correlation study. J Alzheimers Dis. doi:10.3233/JAD-131028 PubMedGoogle Scholar
  5. 5.
    Boeve BF, Boylan KB, Graff-Radford NR, DeJesus-Hernandez M, Knopman DS, Pedraza O, Vemuri P, Jones D, Lowe V, Murray ME, Dickson DW, Josephs KA, Rush BK, Machulda MM, Fields JA, Ferman TJ, Baker M, Rutherford NJ, Adamson J, Wszolek ZK, Adeli A, Savica R, Boot B, Kuntz KM, Gavrilova R, Reeves A, Whitwell J, Kantarci K, Jack CR Jr, Parisi JE, Lucas JA, Petersen RC, Rademakers R (2012) Characterization of frontotemporal dementia and/or amyotrophic lateral sclerosis associated with the GGGGCC repeat expansion in C9ORF72. Brain 135(Pt 3):765–783. doi:10.1093/brain/aws004 PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Castaldo I, Pinelli M, Monticelli A, Acquaviva F, Giacchetti M, Filla A, Sacchetti S, Keller S, Avvedimento VE, Chiariotti L, Cocozza S (2008) DNA methylation in intron 1 of the frataxin gene is related to GAA repeat length and age of onset in Friedreich ataxia patients. J Med Genet 45(12):808–812. doi:10.1136/jmg.2008.058594 PubMedCrossRefGoogle Scholar
  7. 7.
    Chio A, Borghero G, Restagno G, Mora G, Drepper C, Traynor BJ, Sendtner M, Brunetti M, Ossola I, Calvo A, Pugliatti M, Sotgiu MA, Murru MR, Marrosu MG, Marrosu F, Marinou K, Mandrioli J, Sola P, Caponnetto C, Mancardi G, Mandich P, La Bella V, Spataro R, Conte A, Monsurro MR, Tedeschi G, Pisano F, Bartolomei I, Salvi F, Lauria Pinter G, Simone I, Logroscino G, Gambardella A, Quattrone A, Lunetta C, Volanti P, Zollino M, Penco S, Battistini S, Renton AE, Majounie E, Abramzon Y, Conforti FL, Giannini F, Corbo M, Sabatelli M (2012) Clinical characteristics of patients with familial amyotrophic lateral sclerosis carrying the pathogenic GGGGCC hexanucleotide repeat expansion of C9ORF72. Brain 135(Pt 3):784–793. doi:10.1093/brain/awr366 PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    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. doi:10.1002/ana.23946 PubMedGoogle Scholar
  9. 9.
    Cleary JD, Ranum LP (2013) Repeat-associated non-ATG (RAN) translation in neurological disease. Hum Mol Genet 22(R1):R45–R51. doi:10.1093/hmg/ddt371 PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Colak D, Zaninovic N, Cohen MS, Rosenwaks Z, Yang WY, Gerhardt J, Disney MD, Jaffrey SR (2014) Promoter-bound trinucleotide repeat mRNA drives epigenetic silencing in fragile X syndrome. Science 343(6174):1002–1005. doi:10.1126/science.1245831 PubMedCrossRefGoogle Scholar
  11. 11.
    Collins SC, Bray SM, Suhl JA, Cutler DJ, Coffee B, Zwick ME, Warren ST (2010) Identification of novel FMR1 variants by massively parallel sequencing in developmentally delayed males. Am J Med Genet A 152A(10):2512–2520. doi:10.1002/ajmg.a.33626 PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Collins SC, Coffee B, Benke PJ, Berry-Kravis E, Gilbert F, Oostra B, Halley D, Zwick ME, Cutler DJ, Warren ST (2010) Array-based FMR1 sequencing and deletion analysis in patients with a fragile X syndrome-like phenotype. PLoS One 5(3):e9476. doi:10.1371/journal.pone.0009476 PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Cooper-Knock J, Hewitt C, Highley JR, Brockington A, Milano A, Man S, Martindale J, Hartley J, Walsh T, Gelsthorpe C, Baxter L, Forster G, Fox M, Bury J, Mok K, McDermott CJ, Traynor BJ, Kirby J, Wharton SB, Ince PG, Hardy J, Shaw PJ (2012) Clinico-pathological features in amyotrophic lateral sclerosis with expansions in C9ORF72. Brain 135(Pt 3):751–764. doi:10.1093/brain/awr365 PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    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(19):1719–1721. doi:10.1212/01.wnl.0000435295.41974.2e PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    de Vries BB, Jansen CC, Duits AA, Verheij C, Willemsen R, van Hemel JO, van den Ouweland AM, Niermeijer MF, Oostra BA, Halley DJ (1996) Variable FMR1 gene methylation of large expansions leads to variable phenotype in three males from one fragile X family. J Med Genet 33(12):1007–1010PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    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(2):245–256. doi:10.1016/j.neuron.2011.09.011 PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Devys D, Biancalana V, Rousseau F, Boue J, Mandel JL, Oberle I (1992) Analysis of full fragile X mutations in fetal tissues and monozygotic twins indicate that abnormal methylation and somatic heterogeneity are established early in development. Am J Med Genet 43(1–2):208–216PubMedCrossRefGoogle Scholar
  18. 18.
    Dion V, Wilson JH (2009) Instability and chromatin structure of expanded trinucleotide repeats. Trends Genet 25(7):288–297. doi:10.1016/j.tig.2009.04.007 PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Dols-Icardo O, Garcia-Redondo A, Rojas-Garcia R, Sanchez-Valle R, Noguera A, Gomez-Tortosa E, Pastor P, Hernandez I, Esteban-Perez J, Suarez-Calvet M, Anton-Aguirre S, Amer G, Ortega-Cubero S, Blesa R, Fortea J, Alcolea D, Capdevila A, Antonell A, Llado A, Munoz-Blanco JL, Mora JS, Galan-Davila L, Rodriguez De Rivera FJ, Lleo A, Clarimon J (2013) Characterization of the repeat expansion size in C9orf72 in amyotrophic lateral sclerosis and frontotemporal dementia. Hum Mol Genet. doi:10.1093/hmg/ddt460 PubMedGoogle Scholar
  20. 20.
    Donnelly CJ, Zhang PW, Pham JT, Heusler 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(2):415–428. doi:10.1016/j.neuron.2013.10.015 PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Eiges R, Urbach A, Malcov M, Frumkin T, Schwartz T, Amit A, Yaron Y, Eden A, Yanuka O, Benvenisty N, Ben-Yosef D (2007) Developmental study of fragile X syndrome using human embryonic stem cells derived from preimplantation genetically diagnosed embryos. Cell Stem Cell 1(5):568–577. doi:10.1016/j.stem.2007.09.001 PubMedCrossRefGoogle Scholar
  22. 22.
    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(4):487–497. doi:10.1002/ana.22671 PubMedCrossRefGoogle Scholar
  23. 23.
    Fratta P, Mizielinska S, Nicoll AJ, Zloh M, Fisher EMC, Parkinson G, Isaacs AM (2012) C9orf72 hexanucleotide repeat associated with amyotrophic lateral sclerosis and frontotemporal dementia forms RNA G-quadruplexes. Sci Rep. doi:10.1038/srep01016 PubMedPubMedCentralGoogle Scholar
  24. 24.
    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(3):401–409. doi:10.1007/s00401-013-1147-0 PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Gronskov K, Brondum-Nielsen K, Dedic A, Hjalgrim H (2011) A nonsense mutation in FMR1 causing fragile X syndrome. Eur J Hum Genet 19(4):489–491. doi:10.1038/ejhg.2010.223 PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    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(7491):195–200. doi:10.1038/nature13124 PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Hagerman RJ, Hull CE, Safanda JF, Carpenter I, Staley LW, O’Connor RA, Seydel C, Mazzocco MM, Snow K, Thibodeau SN et al (1994) High functioning fragile X males: demonstration of an unmethylated fully expanded FMR-1 mutation associated with protein expression. Am J Med Genet 51(4):298–308. doi:10.1002/ajmg.1320510404 PubMedCrossRefGoogle Scholar
  28. 28.
    Harms M, Benitez BA, Cairns N, Cooper B, Cooper P, Mayo K, Carrell D, Faber K, Williamson J, Bird T, Diaz-Arrastia R, Foroud TM, Boeve BF, Graff-Radford NR, Mayeux R, Chakraverty S, Goate AM, Cruchaga C (2013) C9orf72 hexanucleotide repeat expansions in clinical Alzheimer disease. JAMA Neurol 70(6):736–741. doi:10.1001/2013.jamaneurol.537 PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Harms MB, Cady J, Zaidman C, Cooper P, Bali T, Allred P, Cruchaga C, Baughn M, Libby RT, Pestronk A, Goate A, Ravits J, Baloh RH (2013) Lack of C9ORF72 coding mutations supports a gain of function for repeat expansions in amyotrophic lateral sclerosis. Neurobiol Aging 34(9):2234. doi:10.1016/j.neurobiolaging.2013.03.006. e2213–e2239PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Hsiung GY, DeJesus-Hernandez M, Feldman HH, Sengdy P, Bouchard-Kerr P, Dwosh E, Butler R, Leung B, Fok A, Rutherford NJ, Baker M, Rademakers R, Mackenzie IR (2012) Clinical and pathological features of familial frontotemporal dementia caused by C9ORF72 mutation on chromosome 9p. Brain 135(Pt 3):709–722. doi:10.1093/brain/awr354 PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Khan BK, Yokoyama JS, Takada LT, Sha SJ, Rutherford NJ, Fong JC, Karydas AM, Wu T, Ketelle RS, Baker MC, Hernandez MD, Coppola G, Geschwind DH, Rademakers R, Lee SE, Rosen HJ, Rabinovici GD, Seeley WW, Rankin KP, Boxer AL, Miller BL (2012) Atypical, slowly progressive behavioural variant frontotemporal dementia associated with C9ORF72 hexanucleotide expansion. J Neurol Neurosurg Psychiatry 83(4):358–364. doi:10.1136/jnnp-2011-301883 PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    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(47):E4530–E4539. doi:10.1073/pnas.1318835110 PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Lee EB, Lee VM, Trojanowski JQ (2012) Gains or losses: molecular mechanisms of TDP43-mediated neurodegeneration. Nat Rev Neurosci 13(1):38–50. doi:10.1038/nrn3121 Google Scholar
  34. 34.
    Lee EB, Russ J, Jung H, Elman LB, Chahine LM, Kremens D, Miller BL, Branch Coslett H, Trojanowski JQ, Van Deerlin VM, McCluskey LF (2013) Topography of FUS pathology distinguishes late-onset BIBD from a FTLD-U. Acta Neuropathol Commun 1(9):1–11. doi:10.1186/2051-5960-1-9 PubMedGoogle Scholar
  35. 35.
    Lee Y-B, Chen H-J, Peres João N, Gomez-Deza J, Attig J, talekar M, Troakes C, Nishimura Agnes L, Scotter Emma L, Vance C, Adachi Y, Sardone V, Miller Jack W, Smith Bradley N, Gallo J-M, Ule J, Hirth F, Rogelj B, Houart C, Shaw Christopher E (2013) Hexanucleotide repeats in ALS/FTD form length-dependent RNA foci, sequester RNA binding proteins, and are neurotoxic. Cell reports. doi:10.1016/j.celrep.2013.10.049
  36. 36.
    Li YR, King OD, Shorter J, Gitler AD (2013) Stress granules as crucibles of ALS pathogenesis. J Cell Biol 201(3):361–372. doi:10.1083/jcb.201302044 PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Ling SC, Polymenidou M, Cleveland DW (2013) Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis. Neuron 79(3):416–438. doi:10.1016/j.neuron.2013.07.033 PubMedCrossRefGoogle Scholar
  38. 38.
    Loesch DZ, Huggins R, Hay DA, Gedeon AK, Mulley JC, Sutherland GR (1993) Genotype–phenotype relationships in fragile X syndrome: a family study. Am J Hum Genet 53(5):1064–1073PubMedPubMedCentralGoogle Scholar
  39. 39.
    Mackenzie IR, Arzberger T, Kremmer E, Troost D, Lorenzl S, Mori K, Weng SM, Haass C, Kretzschmar HA, Edbauer D, Neumann M (2013) Dipeptide repeat protein pathology in C9ORF72 mutation cases: clinico-pathological correlations. Acta Neuropathol 126(6):859–879. doi:10.1007/s00401-013-1181-y PubMedCrossRefGoogle Scholar
  40. 40.
    Mackenzie IR, Frick P, Neumann M (2014) The neuropathology associated with repeat expansions in the C9ORF72 gene. Acta Neuropathol 127(3):347–357. doi:10.1007/s00401-013-1232-4 PubMedCrossRefGoogle Scholar
  41. 41.
    Mahoney CJ, Beck J, Rohrer JD, Lashley T, Mok K, Shakespeare T, Yeatman T, Warrington EK, Schott JM, Fox NC, Rossor MN, Hardy J, Collinge J, Revesz T, Mead S, Warren JD (2012) Frontotemporal dementia with the C9ORF72 hexanucleotide repeat expansion: clinical, neuroanatomical and neuropathological features. Brain 135(Pt 3):736–750. doi:10.1093/brain/awr361 PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    McConkie-Rosell A, Lachiewicz AM, Spiridigliozzi GA, Tarleton J, Schoenwald S, Phelan MC, Goonewardena P, Ding X, Brown WT (1993) Evidence that methylation of the FMR-I locus is responsible for variable phenotypic expression of the fragile X syndrome. Am J Hum Genet 53(4):800–809PubMedPubMedCentralGoogle Scholar
  43. 43.
    Merenstein SA, Sobesky WE, Taylor AK, Riddle JE, Tran HX, Hagerman RJ (1996) Molecular–clinical correlations in males with an expanded FMR1 mutation. Am J Med Genet 64(2):388–394. doi:10.1002/(SICI)1096-8628(19960809)64:2<388:AID-AJMG31>3.0.CO;2-9 PubMedCrossRefGoogle Scholar
  44. 44.
    Miller JW, Urbinati CR, Teng-Umnuay P, Stenberg MG, Byrne BJ, Thornton CA, Swanson MS (2000) Recruitment of human muscleblind proteins to (CUG)(n) expansions associated with myotonic dystrophy. EMBO J 19(17):4439–4448. doi:10.1093/emboj/19.17.4439 PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Mori K, Lammich S, Mackenzie IR, Forné I, Zilow S, Kretzschmar H, Edbauer D, Janssens J, Kleinberger G, Cruts M, Herms J, Neumann M, Van Broeckhoven C, Arzberger T, Haass C (2013) hnRNP A3 binds to GGGGCC repeats and is a constituent of p62-positive/TDP43-negative inclusions in the hippocampus of patients with C9orf72 mutations. Acta Neuropathol 125(3):413–423. doi:10.1007/s00401-013-1088-7
  46. 46.
    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(6125):1335–1338. doi:10.1126/science.1232927 PubMedCrossRefGoogle Scholar
  47. 47.
    Murray ME, Bieniek KF, Banks Greenberg M, DeJesus-Hernandez M, Rutherford NJ, van Blitterswijk M, Niemantsverdriet E, Ash PE, Gendron TF, Kouri N, Baker M, Goodman IJ, Petrucelli L, Rademakers R, Dickson DW (2013) Progressive amnestic dementia, hippocampal sclerosis, and mutation in C9ORF72. Acta Neuropathol 126(4):545–554. doi:10.1007/s00401-013-1161-2 PubMedCrossRefGoogle Scholar
  48. 48.
    Myrick L, Nakamoto-Kinoshita M, Lindor N, Kirmani S, Cheng X, Warren S (2014) Fragile X syndrome due to a missense mutation. Eur J Hum Genet. doi:10.1038/ejhg.2013.311
  49. 49.
    O’Donnell WT, Warren ST (2002) A decade of molecular studies of fragile X syndrome. Annu Rev Neurosci 25:315–338. doi:10.1146/annurev.neuro.25.112701.142909 PubMedCrossRefGoogle Scholar
  50. 50.
    Pearson CE, Nichol Edamura K, Cleary JD (2005) Repeat instability: mechanisms of dynamic mutations. Nat Rev Genet 6(10):729–742. doi:10.1038/nrg1689 PubMedCrossRefGoogle Scholar
  51. 51.
    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 multi-molecular RNA G-quadruplex structures. J Biol Chem 288(14):9860–9866. doi:10.1074/jbc.C113.452532 PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Reiss AL, Freund LS, Baumgardner TL, Abrams MT, Denckla MB (1995) Contribution of the FMR1 gene mutation to human intellectual dysfunction. Nat Genet 11(3):331–334. doi:10.1038/ng1195-331 PubMedCrossRefGoogle Scholar
  53. 53.
    Renton AE, Majounie E, Waite A, Simon-Sanchez J, Rollinson S, Gibbs JR, Schymick JC, Laaksovirta H, van Swieten JC, Myllykangas L, Kalimo H, 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, Borghero G, Sabatelli M, Consortium I, 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(2):257–268. doi:10.1016/j.neuron.2011.09.010 PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Rosenbloom KR, Sloan CA, Malladi VS, Dreszer TR, Learned K, Kirkup VM, Wong MC, Maddren M, Fang R, Heitner SG, Lee BT, Barber GP, Harte RA, Diekhans M, Long JC, Wilder SP, Zweig AS, Karolchik D, Kuhn RM, Haussler D, Kent WJ (2013) ENCODE data in the UCSC genome browser: year 5 update. Nucleic Acids Res 41(Database issue):D56–D63. doi:10.1093/nar/gks1172 PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Sareen D, O’Rourke JG, Meera P, Muhammad AK, Grant S, Simpkinson M, Bell S, Carmona S, Ornelas L, Sahabian A, Gendron T, Petrucelli L, Baughn M, Ravits J, Harms MB, Rigo F, Bennett CF, Otis TS, Svendsen CN, Baloh RH (2013) Targeting RNA Foci in iPSC-derived motor neurons from ALS patients with a C9ORF72 repeat expansion. Sci Transl Med 5(208):208ra149. doi:10.1126/scitranslmed.3007529 PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Simon-Sanchez J, Dopper EG, Cohn-Hokke PE, Hukema RK, Nicolaou N, Seelaar H, de Graaf JR, de Koning I, van Schoor NM, Deeg DJ, Smits M, Raaphorst J, van den Berg LH, Schelhaas HJ, De Die-Smulders CE, Majoor-Krakauer D, Rozemuller AJ, Willemsen R, Pijnenburg YA, Heutink P, van Swieten JC (2012) The clinical and pathological phenotype of C9ORF72 hexanucleotide repeat expansions. Brain 135(Pt 3):723–735. doi:10.1093/brain/awr353 PubMedCrossRefGoogle Scholar
  57. 57.
    Smeets HJ, Smits AP, Verheij CE, Theelen JP, Willemsen R, van de Burgt I, Hoogeveen AT, Oosterwijk JC, Oostra BA (1995) Normal phenotype in two brothers with a full FMR1 mutation. Hum Mol Genet 4(11):2103–2108PubMedCrossRefGoogle Scholar
  58. 58.
    Snowden JS, Rollinson S, Thompson JC, Harris JM, Stopford CL, Richardson AM, Jones M, Gerhard A, Davidson YS, Robinson A, Gibbons L, Hu Q, DuPlessis D, Neary D, Mann DM, Pickering-Brown SM (2012) Distinct clinical and pathological characteristics of frontotemporal dementia associated with C9ORF72 mutations. Brain 135(Pt 3):693–708. doi:10.1093/brain/awr355 PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Stepto A, Gallo JM, Shaw CE, Hirth F (2014) Modelling C9ORF72 hexanucleotide repeat expansion in amyotrophic lateral sclerosis and frontotemporal dementia. Acta Neuropathol 127(3):377–389. doi:10.1007/s00401-013-1235-1 PubMedCrossRefGoogle Scholar
  60. 60.
    Straussman R, Nejman D, Roberts D, Steinfeld I, Blum B, Benvenisty N, Simon I, Yakhini Z, Cedar H (2009) Developmental programming of CpG island methylation profiles in the human genome. Nature Struct Mol Biol 16(5):564–571. doi:10.1038/nsmb.1594 CrossRefGoogle Scholar
  61. 61.
    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(6):397–400PubMedCrossRefGoogle Scholar
  62. 62.
    Toledo JB, Van Deerlin VM, Lee EB, Suh E, Baek Y, Robinson JL, Xie SX, McBride J, Wood EM, Schuck T, Irwin DJ, Gross RG, Hurtig H, McCluskey L, Elman L, Karlawish J, Schellenberg G, Chen-Plotkin A, Wolk D, Grossman M, Arnold SE, Shaw LM, Lee VM, Trojanowski JQ (2013) A platform for discovery: the University of Pennsylvania integrated neurodegenerative disease biobank. Alzheimers Dement. doi:10.1016/j.jalz.2013.06.003 PubMedPubMedCentralGoogle Scholar
  63. 63.
    van Blitterswijk M, DeJesus-Hernandez M, Niemantsverdriet E, Murray ME, Heckman MG, Diehl NN, Brown PH, Baker MC, Finch NA, Bauer PO, Serrano G, Beach TG, Josephs KA, Knopman DS, Petersen RC, Boeve BF, Graff-Radford NR, Boylan KB, Petrucelli L, Dickson DW, Rademakers R (2013) Association between repeat sizes and clinical and pathological characteristics in carriers of C9ORF72 repeat expansions (Xpansize-72): a cross-sectional cohort study. Lancet Neurol 12(10):978–988. doi:10.1016/S1474-4422(13)70210-2 PubMedCrossRefGoogle Scholar
  64. 64.
    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. doi:10.1016/j.neurobiolaging.2014.01.016 PubMedPubMedCentralGoogle Scholar
  65. 65.
    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 G4C2 repeat in ALS with a C9orf72 expansion. Am J Hum Genet 92(6):981–989. doi:10.1016/j.ajhg.2013.04.017 PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Xu Z, Poidevin M, Li X, Li Y, Shu L, Nelson DL, Li H, Hales CM, Gearing M, Wingo TS, Jin P (2013) Expanded GGGGCC repeat RNA associated with amyotrophic lateral sclerosis and frontotemporal dementia causes neurodegeneration. Proc Natl Acad Sci USA 110(19):7778–7783. doi:10.1073/pnas.1219643110 PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Elaine Y. Liu
    • 1
    • 2
  • Jenny Russ
    • 1
    • 2
  • Kathryn Wu
    • 1
    • 2
  • Donald Neal
    • 2
  • Eunran Suh
    • 2
  • Anna G. McNally
    • 1
    • 2
  • David J. Irwin
    • 2
    • 3
  • Vivianna M. Van Deerlin
    • 2
  • Edward B. Lee
    • 1
    • 2
  1. 1.Translational Neuropathology Research LaboratoryPerelman School of Medicine at the University of PennsylvaniaPhiladelphiaUSA
  2. 2.Department of Pathology and Laboratory MedicinePerelman School of Medicine at the University of PennsylvaniaPhiladelphiaUSA
  3. 3.Department of NeurologyPerelman School of Medicine at the University of PennsylvaniaPhiladelphiaUSA

Personalised recommendations