dna repeat expansion


Summary: An increase number of repeats of a genomic, tandemly repeated DNA sequence from one generation to the next.

Top Publications

  1. Gatchel J, Zoghbi H. Diseases of unstable repeat expansion: mechanisms and common principles. Nat Rev Genet. 2005;6:743-55 pubmed
    ..In all these diseases, the context of the expanded repeat and the abundance, subcellular localization and interactions of the proteins and RNAs that are affected have key roles in disease-specific phenotypes. ..
  2. Mirkin S. Expandable DNA repeats and human disease. Nature. 2007;447:932-40 pubmed
    ..It is becoming clear that the peculiar structures of repeat-containing transcripts are at the heart of the pathogenesis of these diseases. ..
  3. Lin X, Ashizawa T. SCA10 and ATTCT repeat expansion: clinical features and molecular aspects. Cytogenet Genome Res. 2003;100:184-8 pubmed
  4. Ku S, Soragni E, Campau E, Thomas E, Altun G, Laurent L, et al. Friedreich's ataxia induced pluripotent stem cells model intergenerational GAA?TTC triplet repeat instability. Cell Stem Cell. 2010;7:631-7 pubmed publisher
  5. Fratta P, Poulter M, Lashley T, Rohrer J, Polke J, Beck J, et al. Homozygosity for the C9orf72 GGGGCC repeat expansion in frontotemporal dementia. Acta Neuropathol. 2013;126:401-9 pubmed publisher
    ..Our findings have implications for genetic counselling, highlighting the need to use genetic tests that distinguish C9orf72 homozygosity. ..
  6. Mirkin S. DNA structures, repeat expansions and human hereditary disorders. Curr Opin Struct Biol. 2006;16:351-8 pubmed
    ..It also explains the bias toward repeat expansion or contraction that was observed in different organisms. ..
  7. Reddy K, Zamiri B, Stanley S, Macgregor R, Pearson C. 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. 2013;288:9860-6 pubmed publisher
  8. Kuyumcu Martinez N, Wang G, Cooper T. Increased steady-state levels of CUGBP1 in myotonic dystrophy 1 are due to PKC-mediated hyperphosphorylation. Mol Cell. 2007;28:68-78 pubmed
    ..These results indicate that inappropriate activation of the PKC pathway contributes to the pathogenic effects of a noncoding RNA. ..
  9. Chio A, Borghero G, Restagno G, Mora G, Drepper C, Traynor B, et al. Clinical characteristics of patients with familial amyotrophic lateral sclerosis carrying the pathogenic GGGGCC hexanucleotide repeat expansion of C9ORF72. Brain. 2012;135:784-93 pubmed publisher
    ..Their pedigrees typically display a high frequency of cases with pure frontotemporal dementia, widening the concept of familial amyotrophic lateral sclerosis. ..

More Information


  1. Gijselinck I, Van Langenhove T, van der Zee J, Sleegers K, Philtjens S, Kleinberger G, et al. 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. 2012;11:54-65 pubmed publisher
    ..Unidentified genes probably also contribute to the FTLD-ALS disease spectrum. Full funding sources listed at end of paper (see Acknowledgments). ..
  2. Al Sarraj S, King A, Troakes C, Smith B, Maekawa S, Bodi I, et al. p62 positive, TDP-43 negative, neuronal cytoplasmic and intranuclear inclusions in the cerebellum and hippocampus define the pathology of C9orf72-linked FTLD and MND/ALS. Acta Neuropathol. 2011;122:691-702 pubmed publisher
    ..Our results suggest that proteins other than TDP-43 are binding p62 and aggregating in response to the mutation which may play a mechanistic role in neurodegeneration. ..
  3. DeJesus Hernandez M, Mackenzie I, Boeve B, Boxer A, Baker M, Rutherford N, et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron. 2011;72:245-56 pubmed publisher
    ..Our findings indicate that repeat expansion in C9ORF72 is a major cause of both FTD and ALS. ..
  4. Raheem O, Olufemi S, Bachinski L, Vihola A, Sirito M, Holmlund Hampf J, et al. Mutant (CCTG)n expansion causes abnormal expression of zinc finger protein 9 (ZNF9) in myotonic dystrophy type 2. Am J Pathol. 2010;177:3025-36 pubmed publisher
    ..Although toxic RNA effects likely explain overlapping phenotypic manifestations between DM1 and DM2, abnormal ZNF9 levels in DM2 may account for the differences in DM1...
  5. Arighi A, Fumagalli G, Jacini F, Fenoglio C, Ghezzi L, Pietroboni A, et al. Early onset behavioral variant frontotemporal dementia due to the C9ORF72 hexanucleotide repeat expansion: psychiatric clinical presentations. J Alzheimers Dis. 2012;31:447-52 pubmed publisher
    ..The description of these cases underlines that the hexanucleotide repeat expansion in chromosome 9 could be associated with early onset psychiatric presentations. ..
  6. Savica R, Adeli A, Vemuri P, Knopman D, DeJesus Hernandez M, Rademakers R, et al. Characterization of a family with c9FTD/ALS associated with the GGGGCC repeat expansion in C9ORF72. Arch Neurol. 2012;69:1164-9 pubmed publisher
    ..This report highlights the clinical and neuroimaging characteristics of a family with c9FTD/ALS. Further studies are needed to better understand the phenotypical variability and the cliniconeuroimaging-neuropathologic correlations. ..
  7. Lindquist S, Duno M, Batbayli M, Puschmann A, Braendgaard H, Mardosiene S, et al. Corticobasal and ataxia syndromes widen the spectrum of C9ORF72 hexanucleotide expansion disease. Clin Genet. 2013;83:279-83 pubmed publisher
    ..Our study widens the clinical spectrum of C9ORF72 related disease and confirms the hexanucleotide expansion as a prevalent cause of FTD-ALS disorders. There was no indication of a modifying effect of the ATXN2 gene...
  8. Fratta P, Mizielinska S, Nicoll A, Zloh M, Fisher E, Parkinson G, et al. C9orf72 hexanucleotide repeat associated with amyotrophic lateral sclerosis and frontotemporal dementia forms RNA G-quadruplexes. Sci Rep. 2012;2:1016 pubmed publisher
    ..Here we show using NMR and CD spectroscopy that the C9orf72 hexanucleotide expansion can form a stable G-quadruplex, which has profound implications for disease mechanism in ALS and FTD. ..
  9. Cannella M, Martino T, Simonelli M, Ciammola A, Gradini R, Ciarmiello A, et al. De novo seven extra repeat expanded mutation in the PRNP gene in an Italian patient with early onset dementia. J Neurol Neurosurg Psychiatry. 2007;78:1411-3 pubmed
  10. Greene E, Mahishi L, Entezam A, Kumari D, Usdin K. Repeat-induced epigenetic changes in intron 1 of the frataxin gene and its consequences in Friedreich ataxia. Nucleic Acids Res. 2007;35:3383-90 pubmed
    ..Our results also raise the possibility that the repeat-mediated increases in DNA methylation in the FXN gene in FRDA patients are secondary to the chromatin changes. ..
  11. Buchman V, Cooper Knock J, Connor Robson N, Higginbottom A, Kirby J, Razinskaya O, et al. Simultaneous and independent detection of C9ORF72 alleles with low and high number of GGGGCC repeats using an optimised protocol of Southern blot hybridisation. Mol Neurodegener. 2013;8:12 pubmed publisher
    ..The suggested protocol has sufficient advantages to warrant adoption as a standard for Southern blot hybridisation analysis of GGGGCC repeat expansions in the C9ORF72 locus. ..
  12. Cruts M, Gijselinck I, Van Langenhove T, van der Zee J, Van Broeckhoven C. Current insights into the C9orf72 repeat expansion diseases of the FTLD/ALS spectrum. Trends Neurosci. 2013;36:450-9 pubmed publisher
    ..We review genetic, clinical, and pathological highlights and discuss current insights into the biology of this novel type of repeat expansion disease. ..
  13. Mackenzie I, Arzberger T, Kremmer E, Troost D, Lorenzl S, Mori K, et al. Dipeptide repeat protein pathology in C9ORF72 mutation cases: clinico-pathological correlations. Acta Neuropathol. 2013;126:859-79 pubmed publisher
  14. Wells R, Dere R, Hebert M, Napierala M, Son L. Advances in mechanisms of genetic instability related to hereditary neurological diseases. Nucleic Acids Res. 2005;33:3785-98 pubmed
    ..Furthermore, the newly discovered capacities of certain triplet repeat sequences to cause gross chromosomal rearrangements are discussed. ..
  15. Waite A, Bäumer D, East S, Neal J, Morris H, Ansorge O, et al. Reduced C9orf72 protein levels in frontal cortex of amyotrophic lateral sclerosis and frontotemporal degeneration brain with the C9ORF72 hexanucleotide repeat expansion. Neurobiol Aging. 2014;35:1779.e5-1779.e13 pubmed publisher
    ..These data suggest that a reduction in C9orf72 protein may be a consequence of the disease. ..
  16. Day J, Ricker K, Jacobsen J, Rasmussen L, Dick K, Kress W, et al. Myotonic dystrophy type 2: molecular, diagnostic and clinical spectrum. Neurology. 2003;60:657-64 pubmed
    ..The clinical and molecular parallels between DM1 and DM2 indicate that the multisystemic features common to both diseases are caused by CUG or CCUG expansions expressed at the RNA level. ..
  17. Haeusler A, Donnelly C, Periz G, Simko E, Shaw P, Kim M, et al. C9orf72 nucleotide repeat structures initiate molecular cascades of disease. Nature. 2014;507:195-200 pubmed publisher
  18. Ratti A, Corrado L, Castellotti B, Del Bo R, Fogh I, Cereda C, et al. C9ORF72 repeat expansion in a large Italian ALS cohort: evidence of a founder effect. Neurobiol Aging. 2012;33:2528.e7-14 pubmed publisher
  19. Majounie E, Abramzon Y, Renton A, Keller M, Traynor B, Singleton A. Large C9orf72 repeat expansions are not a common cause of Parkinson's disease. Neurobiol Aging. 2012;33:2527.e1-2 pubmed publisher
    ..No large expansions were identified in our cohort. ..
  20. van Blitterswijk M, DeJesus Hernandez M, Niemantsverdriet E, Murray M, Heckman M, Diehl N, et al. Association between repeat sizes and clinical and pathological characteristics in carriers of C9ORF72 repeat expansions (Xpansize-72): a cross-sectional cohort study. Lancet Neurol. 2013;12:978-88 pubmed publisher
  21. Pamphlett R, Cheong P, Trent R, Yu B. Transmission of C9orf72 hexanucleotide repeat expansions in sporadic amyotrophic lateral sclerosis: an Australian trio study. Neuroreport. 2012;23:556-9 pubmed publisher
    ..Our results suggest that a simple monogenic mechanism is not likely to be the cause of C9orf72 repeat-related SALS. ..
  22. Majounie E, Renton A, Mok K, Dopper E, Waite A, Rollinson S, et al. Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study. Lancet Neurol. 2012;11:323-30 pubmed publisher
    ..Testing for this pathogenic expansion should be considered in the management and genetic counselling of patients with these fatal neurodegenerative diseases. Full funding sources listed at end of paper (see Acknowledgments). ..
  23. Lagier Tourenne C, Baughn M, Rigo F, Sun S, Liu P, Li H, et al. Targeted degradation of sense and antisense C9orf72 RNA foci as therapy for ALS and frontotemporal degeneration. Proc Natl Acad Sci U S A. 2013;110:E4530-9 pubmed publisher
    ..Taken together, these findings support a therapeutic approach by ASO administration to reduce hexanucleotide repeat-containing RNAs and raise the potential importance of targeting expanded RNAs transcribed in both directions. ..
  24. Boeve B, Boylan K, Graff Radford N, DeJesus Hernandez M, Knopman D, Pedraza O, et al. Characterization of frontotemporal dementia and/or amyotrophic lateral sclerosis associated with the GGGGCC repeat expansion in C9ORF72. Brain. 2012;135:765-83 pubmed publisher
    ..While variability exists, most cases with this mutation have a characteristic spectrum of demographic, clinical, neuropsychological, neuroimaging and especially neuropathological findings. ..
  25. Simon Sanchez J, Dopper E, Cohn Hokke P, Hukema R, Nicolaou N, Seelaar H, et al. The clinical and pathological phenotype of C9ORF72 hexanucleotide repeat expansions. Brain. 2012;135:723-35 pubmed publisher
    ..Neuropathological hallmarks include neuronal and glial inclusions, and dystrophic neurites containing transactive response DNA binding protein. Future studies are needed to explain the wide variation in clinical presentation. ..
  26. Schoser B, Kress W, Walter M, Halliger Keller B, Lochmuller H, Ricker K. Homozygosity for CCTG mutation in myotonic dystrophy type 2. Brain. 2004;127:1868-77 pubmed
    ..None of these children have signs or symptoms of disease until the age of 18 years. Homozygosity for the DM2 expansion does not seem to alter the disease phenotype as compared with the heterozygous state. ..
  27. Matsuura T, Fang P, Pearson C, Jayakar P, Ashizawa T, Roa B, et al. Interruptions in the expanded ATTCT repeat of spinocerebellar ataxia type 10: repeat purity as a disease modifier?. Am J Hum Genet. 2006;78:125-9 pubmed
    ..Our findings for SCA10 challenge this convention and suggest that the purity of the expanded repeat element may be a disease modifier. ..
  28. Roze E, Betuing S, Deyts C, Marcon E, Brami Cherrier K, Pages C, et al. Mitogen- and stress-activated protein kinase-1 deficiency is involved in expanded-huntingtin-induced transcriptional dysregulation and striatal death. FASEB J. 2008;22:1083-93 pubmed
    ..We propose that MSK-1 deficiency is involved in transcriptional dysregulation and striatal degeneration. Restoration of its expression and activity may be a new therapeutic target in HD. ..
  29. Saito T, Amakusa Y, Kimura T, Yahara O, Aizawa H, Ikeda Y, et al. Myotonic dystrophy type 2 in Japan: ancestral origin distinct from Caucasian families. Neurogenetics. 2008;9:61-3 pubmed
    ..These data strongly suggest that DM2 expansion mutations originate from separate founders in Europe and Japan and are more widely distributed than previously recognized. ..
  30. Hao M, Akrami K, Wei K, de Diego C, Che N, Ku J, et al. Muscleblind-like 2 (Mbnl2) -deficient mice as a model for myotonic dystrophy. Dev Dyn. 2008;237:403-10 pubmed publisher
    ..Our results support the hypothesis that Muscleblind proteins and specifically MBNL2 contribute to the pathogenesis of human DM. ..
  31. Mahoney C, Beck J, Rohrer J, Lashley T, Mok K, Shakespeare T, et al. Frontotemporal dementia with the C9ORF72 hexanucleotide repeat expansion: clinical, neuroanatomical and neuropathological features. Brain. 2012;135:736-50 pubmed publisher
  32. Entezam A, Biacsi R, Orrison B, Saha T, Hoffman G, Grabczyk E, et al. Regional FMRP deficits and large repeat expansions into the full mutation range in a new Fragile X premutation mouse model. Gene. 2007;395:125-34 pubmed
  33. Dere R, Napierala M, Ranum L, Wells R. Hairpin structure-forming propensity of the (CCTG.CAGG) tetranucleotide repeats contributes to the genetic instability associated with myotonic dystrophy type 2. J Biol Chem. 2004;279:41715-26 pubmed
    ..However, similar to the triplet repeat sequences, the ability of one of the two strands to form a more stable folded structure, in our case the CAGG strand, explains this unorthodox "reversed" behavior. ..
  34. Parekh Olmedo H, Wang J, Gusella J, Kmiec E. Modified single-stranded oligonucleotides inhibit aggregate formation and toxicity induced by expanded polyglutamine. J Mol Neurosci. 2004;24:257-67 pubmed
    ..Our data provide the first evidence that short synthetic oligonucleotides inhibit a fundamental pathological pathway of HD and may provide the basis for a novel therapeutic approach. ..
  35. Pearson C, Nichol Edamura K, Cleary J. Repeat instability: mechanisms of dynamic mutations. Nat Rev Genet. 2005;6:729-42 pubmed
    ..b>DNA repeat expansion mutations are dynamic and ongoing within tissues and across generations...
  36. Murray M, DeJesus Hernandez M, Rutherford N, Baker M, Duara R, Graff Radford N, et al. Clinical and neuropathologic heterogeneity of c9FTD/ALS associated with hexanucleotide repeat expansion in C9ORF72. Acta Neuropathol. 2011;122:673-90 pubmed publisher
    ..Further studies are needed to address the molecular mechanism of clinical and pathological heterogeneity of c9FTD/ALS due to mutations in C9ORF72. ..
  37. Almeida S, Gascon E, Tran H, Chou H, Gendron T, Degroot S, et al. Modeling key pathological features of frontotemporal dementia with C9ORF72 repeat expansion in iPSC-derived human neurons. Acta Neuropathol. 2013;126:385-99 pubmed publisher
  38. Bichara M, Wagner J, Lambert I. Mechanisms of tandem repeat instability in bacteria. Mutat Res. 2006;598:144-63 pubmed
    ..coli. In addition, new experimental data are presented, suggesting that TLS polymerases (PolII, PolIV and PolV) do not contribute significantly to TRI in E. coli. ..
  39. Hawkins J, Kim H, Nason J, Wing R, Wendel J. Differential lineage-specific amplification of transposable elements is responsible for genome size variation in Gossypium. Genome Res. 2006;16:1252-61 pubmed
    ..Like maize, Gossypium has undergone a threefold increase in genome size due to the accumulation of LTR retrotransposons over the 5-10 Myr since its origin. ..
  40. Szczepanek E, Ruchala M, Szaflarski W, Budny B, Kilinska L, Jaroniec M, et al. FOXE1 polyalanine tract length polymorphism in patients with thyroid hemiagenesis and subjects with normal thyroid. Horm Res Paediatr. 2011;75:329-34 pubmed publisher
    ..Therefore, FOXE1-polyAla tract expansion may contribute to the molecular background of familial but not sporadic forms of TH. Further studies are still required to confirm such findings. ..
  41. Xu Z, Poidevin M, Li X, Li Y, Shu L, Nelson D, et al. Expanded GGGGCC repeat RNA associated with amyotrophic lateral sclerosis and frontotemporal dementia causes neurodegeneration. Proc Natl Acad Sci U S A. 2013;110:7778-83 pubmed publisher
    ..Taken together, these findings suggest that the expanded rGGGGCC repeats could cause neurodegeneration, and that Pur ? may play a role in the pathogenesis of amyotrophic lateral sclerosis and frontotemporal dementia. ..
  42. Beck J, Poulter M, Hensman D, Rohrer J, Mahoney C, Adamson G, et al. Large C9orf72 hexanucleotide repeat expansions are seen in multiple neurodegenerative syndromes and are more frequent than expected in the UK population. Am J Hum Genet. 2013;92:345-53 pubmed publisher
    ..C9orf72-related disease might mimic several neurodegenerative disorders and, with potentially 90,000 carriers in the United Kingdom, is more common than previously realized. ..
  43. Mori K, Weng S, Arzberger T, May S, Rentzsch K, Kremmer E, et al. The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS. Science. 2013;339:1335-8 pubmed publisher
    ..These findings directly link the FTLD/ALS-associated genetic mutation to the predominant pathology in patients with C9orf72 hexanucleotide expansion. ..
  44. Van Langenhove T, van der Zee J, Van Broeckhoven C. The molecular basis of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum. Ann Med. 2012;44:817-28 pubmed publisher
    ..In this review, we review the recent advances that support the existence of an FTLD-ALS spectrum, with particular emphasis on the molecular genetic aspect. ..
  45. Rutherford N, Heckman M, DeJesus Hernandez M, Baker M, Soto Ortolaza A, Rayaprolu S, et al. Length of normal alleles of C9ORF72 GGGGCC repeat do not influence disease phenotype. Neurobiol Aging. 2012;33:2950.e5-7 pubmed publisher
    ..No meaningful association between the repeat length of the normal alleles of the GGGGCC repeat in C9ORF72 and disease phenotype or age at onset was observed in C9ORF72 mutation carriers or nonmutation carriers. ..
  46. Brettschneider J, Van Deerlin V, Robinson J, Kwong L, Lee E, Ali Y, et al. Pattern of ubiquilin pathology in ALS and FTLD indicates presence of C9ORF72 hexanucleotide expansion. Acta Neuropathol. 2012;123:825-39 pubmed publisher
    ..Our study indicates that this pathology is associated with alterations in clinical phenotype, and suggests that the presence of C9ORF72 repeat expansions may indicate a worse prognosis in ALS...
  47. Chiò A, Restagno G, Brunetti M, Ossola I, Calvo A, Canosa A, et al. ALS/FTD phenotype in two Sardinian families carrying both C9ORF72 and TARDBP mutations. J Neurol Neurosurg Psychiatry. 2012;83:730-3 pubmed publisher
    ..22 locus. Our data show that in rare neurodegenerative causing genes can co-exist within the same individuals and are associated with a more severe disease course. ..
  48. Usdin K. The biological effects of simple tandem repeats: lessons from the repeat expansion diseases. Genome Res. 2008;18:1011-9 pubmed publisher
  49. Barber R, Hardwick R, Shanks M, Glen C, Mughal S, Voutounou M, et al. The effects of in utero irradiation on mutation induction and transgenerational instability in mice. Mutat Res. 2009;664:6-12 pubmed publisher
    ..The results of this study offer a plausible explanation for the effects of in utero irradiation on the risk of leukaemia and solid cancers after birth. ..
  50. McCullough S, Grant P. Histone acetylation, acetyltransferases, and ataxia--alteration of histone acetylation and chromatin dynamics is implicated in the pathogenesis of polyglutamine-expansion disorders. Adv Protein Chem Struct Biol. 2010;79:165-203 pubmed publisher
  51. Mori K, Arzberger T, Grässer F, Gijselinck I, May S, Rentzsch K, et al. Bidirectional transcripts of the expanded C9orf72 hexanucleotide repeat are translated into aggregating dipeptide repeat proteins. Acta Neuropathol. 2013;126:881-93 pubmed publisher
    ..Novel monoclonal antibodies against poly-(Gly-Arg) will facilitate pathological diagnosis of C9orf72 FTLD/ALS. ..
  52. Sareen D, O Rourke J, Meera P, Muhammad A, Grant S, Simpkinson M, et al. Targeting RNA foci in iPSC-derived motor neurons from ALS patients with a C9ORF72 repeat expansion. Sci Transl Med. 2013;5:208ra149 pubmed publisher
    ..These data show that patient-derived motor neurons can be used to delineate pathogenic events in ALS. ..
  53. Mizielinska S, Lashley T, Norona F, Clayton E, Ridler C, Fratta P, et al. C9orf72 frontotemporal lobar degeneration is characterised by frequent neuronal sense and antisense RNA foci. Acta Neuropathol. 2013;126:845-57 pubmed publisher
    ..These data establish that sense and antisense C9orf72 repeat RNA foci are a consistent and specific feature of C9FTLD, providing new insight into the pathogenesis of C9FTLD. ..