The human genome contains over one million short tandem repeats. Expansion of a subset of these repeat tracts underlies over fifty human disorders, including common genetic causes of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (C9orf72), polyglutamine-associated ataxias and Huntington disease, myotonic dystrophy, and intellectual disability disorders such as Fragile X syndrome. In this Review, we discuss the four major mechanisms by which expansion of short tandem repeats causes disease: loss of function through transcription repression, RNA-mediated gain of function through gelation and sequestration of RNA-binding proteins, gain of function of canonically translated repeat-harbouring proteins, and repeat-associated non-AUG translation of toxic repeat peptides. Somatic repeat instability amplifies these mechanisms and influences both disease age of onset and tissue specificity of pathogenic features. We focus on the crosstalk between these disease mechanisms, and argue that they often synergize to drive pathogenesis. We also discuss the emerging native functions of repeat elements and how their dynamics might contribute to disease at a larger scale than currently appreciated. Lastly, we propose that lynchpins tying these disease mechanisms and native functions together offer promising therapeutic targets with potential shared applications across this class of human disorders.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Lander, E. S. et al. Initial sequencing and analysis of the human genome. Nature 409, 860–921 (2001).
Kruglyak, S., Durrett, R. T., Schug, M. D. & Aquadro, C. F. Equilibrium distributions of microsatellite repeat length resulting from a balance between slippage events and point mutations. Proc. Natl Acad. Sci. USA 95, 10774–10778 (1998).
Quilez, J. et al. Polymorphic tandem repeats within gene promoters act as modifiers of gene expression and DNA methylation in humans. Nucleic Acids Res. 44, 3750–3762 (2016).
Fotsing, S. F. et al. The impact of short tandem repeat variation on gene expression. Nat. Genet. 51, 1652–1659 (2019).
Fu, Y. H. et al. Variation of the CGG repeat at the fragile X site results in genetic instability: resolution of the Sherman paradox. Cell 67, 1047–1058 (1991).
Oberlé, I. et al. Instability of a 550-base pair DNA segment and abnormal methylation in fragile X syndrome. Science 252, 1097–1102 (1991).
Verkerk, A. J. et al. Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell 65, 905–914 (1991).
Kremer, E. J. et al. Mapping of DNA instability at the fragile X to a trinucleotide repeat sequence p(CCG)n. Science 252, 1711–1714 (1991).
La Spada, A. R., Wilson, E. M., Lubahn, D. B., Harding, A. E. & Fischbeck, K. H. Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature 352, 77–79 (1991).
Hannan, A. J. Tandem repeats mediating genetic plasticity in health and disease. Nat. Rev. Genet. 19, 286–298 (2018).
Gymrek, M. A genomic view of short tandem repeats. Curr. Opin. Genet. Dev. 44, 9–16 (2017).
Balzano, E., Pelliccia, F. & Giunta, S. Genome (in)stability at tandem repeats. Semin. Cell Dev. Biol. https://doi.org/10.1016/j.semcdb.2020.10.003 (2020).
La Spada, A. R. & Taylor, J. P. Repeat expansion disease: progress and puzzles in disease pathogenesis. Nat. Rev. Genet. 11, 247–258 (2010).
Nussbacher, J. K., Tabet, R., Yeo, G. W. & Lagier-Tourenne, C. Disruption of RNA metabolism in neurological diseases and emerging therapeutic interventions. Neuron 102, 294–320 (2019).
Khristich, A. N. & Mirkin, S. M. On the wrong DNA track: molecular mechanisms of repeat-mediated genome instability. J. Biol. Chem. 295, 4134–4170 (2020).
Paulson, H. Repeat expansion diseases. Handb. Clin. Neurol. 147, 105–123 (2018).
Wells, R. D. & Ashizawa, T. Genetic Instabilities and Neurological Diseases. (Elsevier, 2006).
Martin, J. P. & Bell, J. A pedigree of mental defect showing sex-linkage. J. Neurol. Psychiatry 6, 154–157 (1943).
Lubs, H. A. A marker X chromosome. Am. J. Hum. Genet. 21, 231–244 (1969).
Eichler, E. E. et al. Evolution of the cryptic FMR1 CGG repeat. Nat. Genet. 11, 301–308 (1995).
Sutcliffe, J. S. et al. DNA methylation represses FMR-1 transcription in fragile X syndrome. Hum. Mol. Genet. 1, 397–400 (1992).
Coffee, B., Zhang, F., Ceman, S., Warren, S. T. & Reines, D. Histone modifications depict an aberrantly heterochromatinized FMR1 gene in fragile X syndrome. Am. J. Hum. Genet. 71, 923–932 (2002).
Gedeon, A. K. et al. Fragile X syndrome without CCG amplification has an FMR1 deletion. Nat. Genet. 1, 341–344 (1992).
De Boulle, K. et al. A point mutation in the FMR-1 gene associated with fragile X mental retardation. Nat. Genet. 3, 31–35 (1993).
Santoro, M. R., Bray, S. M. & Warren, S. T. Molecular mechanisms of fragile X syndrome: a twenty-year perspective. Annu. Rev. Pathol. 7, 219–245 (2012).
Usdin, K. & Kumari, D. Repeat-mediated epigenetic dysregulation of the FMR1 gene in the fragile X-related disorders. Front. Genet. 6, 192 (2015).
Colak, D. et al. Promoter-bound trinucleotide repeat mRNA drives epigenetic silencing in fragile X syndrome. Science 343, 1002–1005 (2014).
Kumari, D. & Usdin, K. Polycomb group complexes are recruited to reactivated FMR1 alleles in Fragile X syndrome in response to FMR1 transcription. Hum. Mol. Genet. 23, 6575–6583 (2014).
Eiges, R. et al. Developmental study of fragile X syndrome using human embryonic stem cells derived from preimplantation genetically diagnosed embryos. Cell Stem Cell 1, 568–577 (2007).
Kumari, D., Sciascia, N. & Usdin, K. Small molecules targeting H3K9 methylation prevent silencing of reactivated FMR1 alleles in fragile X syndrome patient derived cells. Genes 11, (2020).
Liu, X. S. et al. Rescue of fragile X syndrome neurons by DNA methylation editing of the FMR1 gene. Cell 172, 979–992.e6 (2018). Targeting TET1–dCas9 to the CGG repeat of the FMR1 locus drives demethylation and gene reactivation in iPS cell-derived neurons, resulting in phenotypic correction.
Chiurazzi, P., Pomponi, M. G., Willemsen, R., Oostra, B. A. & Neri, G. In vitro reactivation of the FMR1 gene involved in fragile X syndrome. Hum. Mol. Genet. 7, 109–113 (1998).
Godde, J. S., Kass, S. U., Hirst, M. C. & Wolffe, A. P. Nucleosome assembly on methylated CGG triplet repeats in the fragile X mental retardation gene 1 promoter. J. Biol. Chem. 271, 24325–24328 (1996).
Liu, E. Y. et al. C9orf72 hypermethylation protects against repeat expansion-associated pathology in ALS/FTD. Acta Neuropathol. 128, 525–541 (2014).
Xi, Z. et al. Hypermethylation of the CpG island near the G4C2 repeat in ALS with a C9orf72 expansion. Am. J. Hum. Genet. 92, 981–989 (2013).
Russ, J. et al. Hypermethylation of repeat expanded C9orf72 is a clinical and molecular disease modifier. Acta Neuropathol. 129, 39–52 (2015).
Xi, Z. et al. The C9orf72 repeat expansion itself is methylated in ALS and FTLD patients. Acta Neuropathol. 129, 715–727 (2015).
Gijselinck, I. et al. The C9orf72 repeat size correlates with onset age of disease, DNA methylation and transcriptional downregulation of the promoter. Mol. Psychiatry 21, 1112–1124 (2016).
Gu, Y., Shen, Y., Gibbs, R. A. & Nelson, D. L. Identification of FMR2, a novel gene associated with the FRAXE CCG repeat and CpG island. Nat. Genet. 13, 109–113 (1996).
Gecz, J., Gedeon, A. K., Sutherland, G. R. & Mulley, J. C. Identification of the gene FMR2, associated with FRAXE mental retardation. Nat. Genet. 13, 105–108 (1996).
Campuzano, V. et al. Friedreich’s ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science 271, 1423–1427 (1996).
Gottesfeld, J. M. Molecular mechanisms and therapeutics for the GAA·TTC expansion disease Friedreich ataxia. Neurother. J. Am. Soc. Exp. Neurother. 16, 1032–1049 (2019).
Bidichandani, S. I., Ashizawa, T. & Patel, P. I. The GAA triplet-repeat expansion in Friedreich ataxia interferes with transcription and may be associated with an unusual DNA structure. Am. J. Hum. Genet. 62, 111–121 (1998).
Rodden, L. N. et al. Methylated and unmethylated epialleles support variegated epigenetic silencing in Friedreich ataxia. Hum. Mol. Genet. 29, 3818–3829 (2021).
Sakamoto, N. et al. Sticky DNA: self-association properties of long GAA.TTC repeats in R.R.Y triplex structures from Friedreich’s ataxia. Mol. Cell 3, 465–475 (1999).
De Biase, I., Chutake, Y. K., Rindler, P. M. & Bidichandani, S. I. Epigenetic silencing in Friedreich ataxia is associated with depletion of CTCF (CCCTC-binding factor) and antisense transcription. PLoS ONE 4, e7914 (2009).
Mikaeili, H., Sandi, M., Bayot, A., Al-Mahdawi, S. & Pook, M. A. FAST-1 antisense RNA epigenetically alters FXN expression. Sci. Rep. 8, 17217 (2018).
Eimer, H. et al. RNA-dependent epigenetic silencing directs transcriptional downregulation caused by intronic repeat expansions. Cell 174, 1095–1105.e11 (2018).
Li, L., Matsui, M. & Corey, D. R. Activating frataxin expression by repeat-targeted nucleic acids. Nat. Commun. 7, 10606 (2016).
Punga, T. & Bühler, M. Long intronic GAA repeats causing Friedreich ataxia impede transcription elongation. EMBO Mol. Med. 2, 120–129 (2010).
Kim, E., Napierala, M. & Dent, S. Y. R. Hyperexpansion of GAA repeats affects post-initiation steps of FXN transcription in Friedreich’s ataxia. Nucleic Acids Res. 39, 8366–8377 (2011).
Kumari, D., Biacsi, R. E. & Usdin, K. Repeat expansion affects both transcription initiation and elongation in Friedreich ataxia cells. J. Biol. Chem. 286, 4209–4215 (2011).
Reddy, K. et al. Determinants of R-loop formation at convergent bidirectionally transcribed trinucleotide repeats. Nucleic Acids Res. 39, 1749–1762 (2011).
Loomis, E. W., Sanz, L. A., Chédin, F. & Hagerman, P. J. Transcription-associated R-loop formation across the human FMR1 CGG-repeat region. PLOS Genet. 10, e1004294 (2014).
Abu Diab, M. et al. The G-rich repeats in FMR1 and C9orf72 loci are hotspots for local unpairing of DNA. Genetics 210, 1239–1252 (2018).
Robin, G. et al. Calcium dysregulation and Cdk5-ATM pathway involved in a mouse model of fragile X-associated tremor/ataxia syndrome. Hum. Mol. Genet. 26, 2649–2666 (2017).
Farg, M. A., Konopka, A., Soo, K. Y., Ito, D. & Atkin, J. D. The DNA damage response (DDR) is induced by the C9orf72 repeat expansion in amyotrophic lateral sclerosis. Hum. Mol. Genet. 26, 2882–2896 (2017).
Haeusler, A. R. et al. C9orf72 nucleotide repeat structures initiate molecular cascades of disease. Nature 507, 195–200 (2014).
Lin, Y., Dent, S. Y. R., Wilson, J. H., Wells, R. D. & Napierala, M. R loops stimulate genetic instability of CTG.CAG repeats. Proc. Natl Acad. Sci. USA 107, 692–697 (2010).
Massey, T. H. & Jones, L. The central role of DNA damage and repair in CAG repeat diseases. Dis. Model. Mech. 11, dmm031930 (2018).
Askeland, G. et al. Increased nuclear DNA damage precedes mitochondrial dysfunction in peripheral blood mononuclear cells from Huntington’s disease patients. Sci. Rep. 8, 9817 (2018).
Moshell, A. N., Tarone, R. E., Barrett, S. F. & Robbins, J. H. Radiosensitivity in Huntington’s disease: implications for pathogenesis and presymptomatic diagnosis. Lancet Lond. Engl. 1, 9–11 (1980).
Xiao, H. et al. A polyglutamine expansion disease protein sequesters PTIP to attenuate DNA repair and increase genomic instability. Hum. Mol. Genet. 21, 4225–4236 (2012).
López Castel, A., Cleary, J. D. & Pearson, C. E. Repeat instability as the basis for human diseases and as a potential target for therapy. Nat. Rev. Mol. Cell Biol. 11, 165–170 (2010).
Reddy, K. et al. Processing of double-R-loops in (CAG)·(CTG) and C9orf72 (GGGGCC)·(GGCCCC) repeats causes instability. Nucleic Acids Res. 42, 10473–10487 (2014).
Pearson, C. E., Ewel, A., Acharya, S., Fishel, R. A. & Sinden, R. R. Human MSH2 binds to trinucleotide repeat DNA structures associated with neurodegenerative diseases. Hum. Mol. Genet. 6, 1117–1123 (1997).
Keogh, N., Chan, K. Y., Li, G.-M. & Lahue, R. S. MutSβ abundance and Msh3 ATP hydrolysis activity are important drivers of CTG•CAG repeat expansions. Nucleic Acids Res. 45, 10068–10078 (2017).
Neil, A. J. et al. Replication-independent instability of Friedreich’s ataxia GAA repeats during chronological aging. Proc. Natl Acad. Sci. USA 118, e2013080118 (2021).
Gonitel, R. et al. DNA instability in postmitotic neurons. Proc. Natl Acad. Sci. USA 105, 3467–3472 (2008).
Genetic Modifiers of Huntington’s Disease (GeM-HD) Consortium. Identification of genetic factors that modify clinical onset of Huntington’s disease. Cell 162, 516–526 (2015).
Lee, J.-M. et al. A modifier of Huntington’s disease onset at the MLH1 locus. Hum. Mol. Genet. 26, 3859–3867 (2017).
Bettencourt, C. et al. DNA repair pathways underlie a common genetic mechanism modulating onset in polyglutamine diseases: DNA repair pathways modify polyQ disease onset. Ann. Neurol. 79, 983–990 (2016).
Kovalenko, M. et al. Msh2 acts in medium-spiny striatal neurons as an enhancer of CAG instability and mutant huntingtin phenotypes in Huntington’s disease knock-in mice. PLoS ONE 7, e44273 (2012).
Pinto, R. M. et al. Mismatch repair genes Mlh1 and Mlh3 modify CAG instability in Huntington’s disease mice: genome-wide and candidate approaches. PLoS Genet. 9, e1003930 (2013).
Nakamori, M. et al. A slipped-CAG DNA-binding small molecule induces trinucleotide-repeat contractions in vivo. Nat. Genet. 52, 146–159 (2020). Identification of small-molecule binders to CTG/CAG slip-outs that form during repeat transcription and replication reveals that the small molecules favoured MMR-dependent repeat contraction.
Taneja, K. L., McCurrach, M., Schalling, M., Housman, D. & Singer, R. H. Foci of trinucleotide repeat transcripts in nuclei of myotonic dystrophy cells and tissues. J. Cell Biol. 128, 995–1002 (1995).
Zhang, N. & Ashizawa, T. RNA toxicity and foci formation in microsatellite expansion diseases. Curr. Opin. Genet. Dev. 44, 17–29 (2017).
White, M. C. et al. Inactivation of hnRNP K by expanded intronic AUUCU repeat induces apoptosis via translocation of PKCδ to mitochondria in spinocerebellar ataxia 10. PLOS Genet. 6, e1000984 (2010).
Mizielinska, S. et al. C9orf72 frontotemporal lobar degeneration is characterised by frequent neuronal sense and antisense RNA foci. Acta Neuropathol. 126, 845–857 (2013).
Cooper-Knock, J. et al. Antisense RNA foci in the motor neurons of C9ORF72-ALS patients are associated with TDP-43 proteinopathy. Acta Neuropathol. 130, 63–75 (2015).
Burguete, A. S. et al. GGGGCC microsatellite RNA is neuritically localized, induces branching defects, and perturbs transport granule function. eLife 4, e08881 (2015).
Mori, K. et al. Bidirectional transcripts of the expanded C9orf72 hexanucleotide repeat are translated into aggregating dipeptide repeat proteins. Acta Neuropathol. 126, 881–893 (2013).
Botta, A. et al. The CTG repeat expansion size correlates with the splicing defects observed in muscles from myotonic dystrophy type 1 patients. J. Med. Genet. 45, 639–646 (2008).
Wojciechowska, M. & Krzyzosiak, W. J. Cellular toxicity of expanded RNA repeats: focus on RNA foci. Hum. Mol. Genet. 20, 3811–3821 (2011).
Krzyzosiak, W. J. et al. Triplet repeat RNA structure and its role as pathogenic agent and therapeutic target. Nucleic Acids Res. 40, 11–26 (2012).
Fratta, P. et al. C9orf72 hexanucleotide repeat associated with amyotrophic lateral sclerosis and frontotemporal dementia forms RNA G-quadruplexes. Sci. Rep. 2, 1016 (2012).
Reddy, K., Zamiri, B., Stanley, S. Y. R., Macgregor, R. B. & Pearson, C. E. 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 (2013).
Conlon, E. G. et al. The C9ORF72 GGGGCC expansion forms RNA G-quadruplex inclusions and sequesters hnRNP H to disrupt splicing in ALS brains. eLife 5, e17820 (2016).
Mooers, B. H. M., Logue, J. S. & Berglund, J. A. The structural basis of myotonic dystrophy from the crystal structure of CUG repeats. Proc. Natl Acad. Sci. USA 102, 16626–16631 (2005).
Tian, B. et al. Expanded CUG repeat RNAs form hairpins that activate the double-stranded RNA-dependent protein kinase PKR. RNA 6, 79–87 (2000).
van Cruchten, R. T. P., Wieringa, B. & Wansink, D. G. Expanded CUG repeats in DMPK transcripts adopt diverse hairpin conformations without influencing the structure of the flanking sequences. RNA 25, 481–495 (2019).
Jain, A. & Vale, R. D. RNA phase transitions in repeat expansion disorders. Nature 546, 243–247 (2017). Repeat RNAs form phase-separated droplets through gelation in vitro and in nuclei, with variable properties depending on repeat length and sequence.
Querido, E., Gallardo, F., Beaudoin, M., Ménard, C. & Chartrand, P. Stochastic and reversible aggregation of mRNA with expanded CUG-triplet repeats. J. Cell Sci. 124, 1703–1714 (2011).
Miller, J. W. et al. Recruitment of human muscleblind proteins to (CUG)n expansions associated with myotonic dystrophy. EMBO J. 19, 4439–4448 (2000).
Van Treeck, B. & Parker, R. Emerging roles for intermolecular RNA-RNA interactions in RNP assemblies. Cell 174, 791–802 (2018).
Li, P. et al. Phase transitions in the assembly of multivalent signalling proteins. Nature 483, 336–340 (2012).
Banjade, S. & Rosen, M. K. Phase transitions of multivalent proteins can promote clustering of membrane receptors. eLife 3, e04123 (2014).
Lin, Y., Protter, D. S. W., Rosen, M. K. & Parker, R. Formation and maturation of phase-separated liquid droplets by RNA-binding proteins. Mol. Cell 60, 208–219 (2015).
Loughlin, F. E. et al. Tandem RNA binding sites induce self-association of the stress granule marker protein TIA-1. Nucleic Acids Res. 49, 2403–2417 (2021).
Rhine, K., Vidaurre, V. & Myong, S. RNA droplets. Annu. Rev. Biophys. 49, 247–265 (2020).
Wang, E. T. et al. Transcriptome alterations in myotonic dystrophy skeletal muscle and heart. Hum. Mol. Genet. 28, 1312–1321 (2019).
Kanadia, R. N. et al. A muscleblind knockout model for myotonic dystrophy. Science 302, 1978–1980 (2003).
Mankodi, A. et al. Myotonic dystrophy in transgenic mice expressing an expanded CUG repeat. Science 289, 1769–1773 (2000).
Kanadia, R. N. et al. Reversal of RNA missplicing and myotonia after muscleblind overexpression in a mouse poly(CUG) model for myotonic dystrophy. Proc. Natl Acad. Sci. USA 103, 11748–11753 (2006). Kanadia et al. (2003) and Kanadia et al. (2006) establish in mice that sequestration of MBNL protein by CUG repeat RNA is sufficient to explain most of the muscle phenotypes observed in DM1.
Cooper-Knock, J. et al. Sequestration of multiple RNA recognition motif-containing proteins by C9orf72 repeat expansions. Brain J. Neurol. 137, 2040–2051 (2014).
Lee, Y.-B. et al. Hexanucleotide repeats in ALS/FTD form length-dependent RNA foci, sequester RNA binding proteins, and are neurotoxic. Cell Rep. 5, 1178–1186 (2013).
Zhang, K. et al. The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature 525, 56–61 (2015).
Mori, K. et al. 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, 413–423 (2013).
Sellier, C. et al. Sequestration of DROSHA and DGCR8 by expanded CGG RNA repeats alters microRNA processing in fragile X-associated tremor/ataxia syndrome. Cell Rep. 3, 869–880 (2013).
Sofola, O. A. et al. RNA-binding proteins hnRNP A2/B1 and CUGBP1 suppress fragile X CGG premutation repeat-induced neurodegeneration in a Drosophila model of FXTAS. Neuron 55, 565–571 (2007).
Jin, P. et al. Pur alpha binds to rCGG repeats and modulates repeat-mediated neurodegeneration in a Drosophila model of fragile X tremor/ataxia syndrome. Neuron 55, 556–564 (2007).
Batra, R. et al. Loss of MBNL leads to disruption of developmentally regulated alternative polyadenylation in RNA-mediated disease. Mol. Cell 56, 311–322 (2014).
Prudencio, M. et al. Distinct brain transcriptome profiles in C9orf72-associated and sporadic ALS. Nat. Neurosci. 18, 1175–1182 (2015).
Masuda, A. et al. CUGBP1 and MBNL1 preferentially bind to 3′ UTRs and facilitate mRNA decay. Sci. Rep. 2, 209 (2012).
Farina, K. L., Huttelmaier, S., Musunuru, K., Darnell, R. & Singer, R. H. Two ZBP1 KH domains facilitate beta-actin mRNA localization, granule formation, and cytoskeletal attachment. J. Cell Biol. 160, 77–87 (2003).
Wang, E. T. et al. Transcriptome-wide regulation of pre-mRNA splicing and mRNA localization by muscleblind proteins. Cell 150, 710–724 (2012).
Taliaferro, J. M. et al. Distal alternative last exons localize mRNAs to neural projections. Mol. Cell 61, 821–833 (2016).
Müller-McNicoll, M., Rossbach, O., Hui, J. & Medenbach, J. Auto-regulatory feedback by RNA-binding proteins. J. Mol. Cell Biol. 11, 930–939 (2019).
Konieczny, P., Stepniak-Konieczna, E. & Sobczak, K. MBNL expression in autoregulatory feedback loops. RNA Biol. 15, 1–8 (2018).
de Mezer, M., Wojciechowska, M., Napierala, M., Sobczak, K. & Krzyzosiak, W. J. Mutant CAG repeats of huntingtin transcript fold into hairpins, form nuclear foci and are targets for RNA interference. Nucleic Acids Res. 39, 3852–3863 (2011).
Mykowska, A., Sobczak, K., Wojciechowska, M., Kozlowski, P. & Krzyzosiak, W. J. CAG repeats mimic CUG repeats in the misregulation of alternative splicing. Nucleic Acids Res. 39, 8938–8951 (2011).
Gendron, T. F. et al. 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 (2013).
Kino, Y. et al. Nuclear localization of MBNL1: splicing-mediated autoregulation and repression of repeat-derived aberrant proteins. Hum. Mol. Genet. 24, 740–756 (2015).
Tran, H. et al. Differential toxicity of nuclear RNA foci versus dipeptide repeat proteins in a Drosophila model of C9ORF72 FTD/ALS. Neuron 87, 1207–1214 (2015).
Thornton, C. A., Johnson, K. & Moxley, R. T. Myotonic dystrophy patients have larger CTG expansions in skeletal muscle than in leukocytes. Ann. Neurol. 35, 104–107 (1994).
Otero, B. A. et al. Transcriptome alterations in myotonic dystrophy frontal cortex. Cell Rep. 34, (2021).
Sellier, C. et al. rbFOX1/MBNL1 competition for CCUG RNA repeats binding contributes to myotonic dystrophy type 1/type 2 differences. Nat. Commun. 9, 2009 (2018). RBFOX proteins compete with MBNL proteins for binding sites on CCUG repeat RNAs, offering a novel mechanism by which RBP sequestration and toxicity can be attenuated through competition between proteins.
Carrell, S. T. et al. Dmpk gene deletion or antisense knockdown does not compromise cardiac or skeletal muscle function in mice. Hum. Mol. Genet. 25, 4328–4338 (2016).
Hsu, T.-C. et al. Deactivation of TBP contributes to SCA17 pathogenesis. Hum. Mol. Genet. 23, 6878–6893 (2014).
Lieberman, A. P., Shakkottai, V. G. & Albin, R. L. Polyglutamine repeats in neurodegenerative diseases. Annu. Rev. Pathol. 14, 1–27 (2019).
Bäuerlein, F. J. B. et al. In situ architecture and cellular interactions of polyQ inclusions. Cell 171, 179–187.e10 (2017).
Peskett, T. R. et al. A liquid to solid phase transition underlying pathological huntingtin exon1 aggregation. Mol. Cell 70, 588–601.e6 (2018).
Scherzinger, E. et al. Huntingtin-encoded polyglutamine expansions form amyloid-like protein aggregates in vitro and in vivo. Cell 90, 549–558 (1997).
Paulson, H. L. et al. Intranuclear inclusions of expanded polyglutamine protein in spinocerebellar ataxia type 3. Neuron 19, 333–344 (1997).
Ordway, J. M. et al. Ectopically expressed CAG repeats cause intranuclear inclusions and a progressive late onset neurological phenotype in the mouse. Cell 91, 753–763 (1997).
Mangiarini, L. et al. Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell 87, 493–506 (1996).
Schilling, G. et al. Intranuclear inclusions and neuritic aggregates in transgenic mice expressing a mutant N-terminal fragment of huntingtin. Hum. Mol. Genet. 8, 397–407 (1999).
Yamamoto, A., Lucas, J. J. & Hen, R. Reversal of neuropathology and motor dysfunction in a conditional model of Huntington’s disease. Cell 101, 57–66 (2000).
Riley, B. E. & Orr, H. T. Polyglutamine neurodegenerative diseases and regulation of transcription: assembling the puzzle. Genes Dev. 20, 2183–2192 (2006).
Katsuno, M. et al. Reversible disruption of dynactin 1-mediated retrograde axonal transport in polyglutamine-induced motor neuron degeneration. J. Neurosci. 26, 12106–12117 (2006).
Katsuno, M. et al. Testosterone reduction prevents phenotypic expression in a transgenic mouse model of spinal and bulbar muscular atrophy. Neuron 35, 843–854 (2002).
Montie, H. L. et al. Cytoplasmic retention of polyglutamine-expanded androgen receptor ameliorates disease via autophagy in a mouse model of spinal and bulbar muscular atrophy. Hum. Mol. Genet. 18, 1937–1950 (2009).
Palazzolo, I. et al. Akt blocks ligand binding and protects against expanded polyglutamine androgen receptor toxicity. Hum. Mol. Genet. 16, 1593–1603 (2007).
Irwin, S. et al. RNA association and nucleocytoplasmic shuttling by ataxin-1. J. Cell Sci. 118, 233–242 (2005).
Lam, Y. C. et al. ATAXIN-1 interacts with the repressor Capicua in its native complex to cause SCA1 neuropathology. Cell 127, 1335–1347 (2006).
Klement, I. A. et al. Ataxin-1 nuclear localization and aggregation: role in polyglutamine-induced disease in SCA1 transgenic mice. Cell 95, 41–53 (1998).
Lai, S., O’Callaghan, B., Zoghbi, H. Y. & Orr, H. T. 14-3-3 binding to ataxin-1(ATXN1) regulates its dephosphorylation at Ser-776 and transport to the nucleus. J. Biol. Chem. 286, 34606–34616 (2011).
Emamian, E. S. et al. Serine 776 of ataxin-1 is Critical for polyglutamine-induced disease in SCA1 transgenic mice. Neuron 38, 375–387 (2003).
Duvick, L. et al. SCA1-like disease in mice expressing wild-type ataxin-1 with a serine to aspartic acid replacement at residue 776. Neuron 67, 929–935 (2010). Altering the phosphorylation state of ATXN1is sufficient to elicit toxicity even in the absence of polyQ expansion, confirming that aberrant native-protein function has a role in pathogenesis.
Williams, A. J. & Paulson, H. L. Polyglutamine neurodegeneration: protein misfolding revisited. Trends Neurosci. 31, 521–528 (2008).
Klockgether, T., Mariotti, C. & Paulson, H. L. Spinocerebellar ataxia. Nat. Rev. Dis. Prim. 5, 24 (2019).
Zu, T. et al. Non-ATG-initiated translation directed by microsatellite expansions. Proc. Natl Acad. Sci. USA 108, 260–265 (2011). Repeat RNAs can be translated in the absence of an AUG start codon in many repeat expansion disorders.
Todd, P. K. et al. CGG repeat-associated translation mediates neurodegeneration in fragile X tremor ataxia syndrome. Neuron 78, 440–455 (2013).
Ash, P. E. A. et al. Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS. Neuron 77, 639–646 (2013).
Mori, K. et al. The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS. Science 339, 1335–1338 (2013).
Bañez-Coronel, M. et al. RAN translation in Huntington disease. Neuron 88, 667–677 (2015).
Zu, T. et al. RAN translation regulated by muscleblind proteins in myotonic dystrophy type 2. Neuron 95, 1292–1305.e5 (2017).
Soragni, E. et al. Repeat-associated non-ATG (RAN) translation in Fuchs’ endothelial corneal dystrophy. Invest. Ophthalmol. Vis. Sci. 59, 1888–1896 (2018).
Ishiguro, T. et al. Regulatory role of RNA chaperone TDP-43 for RNA misfolding and repeat-associated translation in SCA31. Neuron 94, 108–124.e7 (2017).
Zu, T. et al. RAN proteins and RNA foci from antisense transcripts in C9ORF72 ALS and frontotemporal dementia. Proc. Natl Acad. Sci. USA 110, E4968–E4977 (2013).
Krans, A., Kearse, M. G. & Todd, P. K. Repeat-associated non-AUG translation from antisense CCG repeats in fragile X tremor/ataxia syndrome. Ann. Neurol. 80, 871–881 (2016).
Jackson, R. J., Hellen, C. U. T. & Pestova, T. V. The mechanism of eukaryotic translation initiation and principles of its regulation. Nat. Rev. Mol. Cell Biol. 11, 113–127 (2010).
Kearse, M. G. et al. CGG repeat-associated non-AUG translation utilizes a cap-dependent scanning mechanism of initiation to produce toxic proteins. Mol. Cell 62, 314–322 (2016).
Sellier, C. et al. Translation of expanded CGG repeats into FMRpolyG is pathogenic and may contribute to fragile X tremor ataxia syndrome. Neuron 93, 331–347 (2017).
Linsalata, A. E. et al. DDX3X and specific initiation factors modulate FMR1 repeat-associated non-AUG-initiated translation. EMBO Rep. 20, e47498 (2019).
Kearse, M. G. & Wilusz, J. E. Non-AUG translation: a new start for protein synthesis in eukaryotes. Genes Dev. 31, 1717–1731 (2017).
Green, K. M. et al. RAN translation at C9orf72-associated repeat expansions is selectively enhanced by the integrated stress response. Nat. Commun. 8, 2005 (2017).
Tabet, R. et al. CUG initiation and frameshifting enable production of dipeptide repeat proteins from ALS/FTD C9ORF72 transcripts. Nat. Commun. 9, 152 (2018).
Sonobe, Y. et al. Translation of dipeptide repeat proteins from the C9ORF72 expanded repeat is associated with cellular stress. Neurobiol. Dis. 116, 155–165 (2018).
Westergard, T. et al. Repeat-associated non-AUG translation in C9orf72-ALS/FTD is driven by neuronal excitation and stress. EMBO Mol. Med. 11, (2019).
Cheng, W. et al. C9ORF72 GGGGCC repeat-associated non-AUG translation is upregulated by stress through eIF2α phosphorylation. Nat. Commun. 9, 51 (2018).
Kwan, T. & Thompson, S. R. Noncanonical translation initiation in éukaryotes. Cold Spring Harb. Perspect. Biol. 11, (2019).
Yamada, S. B. et al. RPS25 is required for efficient RAN translation of C9orf72 and other neurodegenerative disease-associated nucleotide repeats. Nat. Neurosci. 22, 1383–1388 (2019).
May, S. et al. C9orf72 FTLD/ALS-associated Gly-Ala dipeptide repeat proteins cause neuronal toxicity and Unc119 sequestration. Acta Neuropathol. 128, 485–503 (2014).
Wen, X. et al. Antisense proline-arginine RAN dipeptides linked to C9ORF72-ALS/FTD form toxic nuclear aggregates that initiate in vitro and in vivo neuronal death. Neuron 84, 1213–1225 (2014).
Mizielinska, S. et al. C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins. Science 345, 1192–1194 (2014).
Oh, S. Y. et al. RAN translation at CGG repeats induces ubiquitin proteasome system impairment in models of fragile X-associated tremor ataxia syndrome. Hum. Mol. Genet. 24, 4317–4326 (2015).
Hukema, R. K. et al. Reversibility of neuropathology and motor deficits in an inducible mouse model for FXTAS. Hum. Mol. Genet. 24, 4948–4957 (2015).
Castro, H. et al. Selective rescue of heightened anxiety but not gait ataxia in a premutation 90CGG mouse model of Fragile X-associated tremor/ataxia syndrome. Hum. Mol. Genet. 26, 2133–2145 (2017).
Rodriguez, C. M. et al. A native function for RAN translation and CGG repeats in regulating fragile X protein synthesis. Nat. Neurosci. 23, 386–397 (2020). Selective targeting of RAN translation initiation with non-cleaving ASOs suppresses repeat toxicity while boosting FMRP production in human neurons, establishing a native role for RAN translation in regulation of neuronal protein synthesis.
Jovičić, A. et al. Modifiers of C9orf72 dipeptide repeat toxicity connect nucleocytoplasmic transport defects to FTD/ALS. Nat. Neurosci. 18, 1226–1229 (2015).
Lee, K.-H. et al. C9orf72 dipeptide repeats impair the assembly, dynamics, and function of membrane-less organelles. Cell 167, 774–788.e17 (2016).
Zhang, Y.-J. et al. Aggregation-prone c9FTD/ALS poly(GA) RAN-translated proteins cause neurotoxicity by inducing ER stress. Acta Neuropathol. 128, 505–524 (2014).
Yamakawa, M. et al. Characterization of the dipeptide repeat protein in the molecular pathogenesis of c9FTD/ALS. Hum. Mol. Genet. 24, 1630–1645 (2015).
Tao, Z. et al. Nucleolar stress and impaired stress granule formation contribute to C9orf72 RAN translation-induced cytotoxicity. Hum. Mol. Genet. 24, 2426–2441 (2015).
Yang, D. et al. FTD/ALS-associated poly(GR) protein impairs the Notch pathway and is recruited by poly(GA) into cytoplasmic inclusions. Acta Neuropathol. 130, 525–535 (2015).
Kanekura, K. et al. Poly-dipeptides encoded by the C9ORF72 repeats block global protein translation. Hum. Mol. Genet. 25, 1803–1813 (2016).
Boeynaems, S. et al. Drosophila screen connects nuclear transport genes to DPR pathology in c9ALS/FTD. Sci. Rep. 6, 20877 (2016).
Zhang, Y.-J. et al. Poly(GR) impairs protein translation and stress granule dynamics in C9orf72-associated frontotemporal dementia and amyotrophic lateral sclerosis. Nat. Med. 24, 1136–1142 (2018).
Hao, Z. et al. Motor dysfunction and neurodegeneration in a C9orf72 mouse line expressing poly-PR. Nat. Commun. 10, 2906 (2019).
Zhang, Y.-J. et al. Heterochromatin anomalies and double-stranded RNA accumulation underlie C9orf72 poly(PR) toxicity. Science 363, eaav2606 (2019).
Flores, B. N. et al. Distinct C9orf72-associated dipeptide repeat structures correlate with neuronal toxicity. PLoS ONE 11, e0165084 (2016).
Ohki, Y. et al. Glycine-alanine dipeptide repeat protein contributes to toxicity in a zebrafish model of C9orf72 associated neurodegeneration. Mol. Neurodegener. 12, 6 (2017).
Guo, Q. et al. In situ structure of neuronal C9orf72 poly-GA aggregates reveals proteasome recruitment. Cell 172, 696–705.e12 (2018).
Freibaum, B. D. & Taylor, J. P. The role of dipeptide repeats in C9ORF72-related ALS-FTD. Front. Mol. Neurosci. 10, 35 (2017).
Nguyen, L., Cleary, J. D. & Ranum, L. P. W. Repeat-associated non-ATG translation: molecular mechanisms and contribution to neurological disease. Annu. Rev. Neurosci. 42, 227–247 (2019).
Odeh, H. M. & Shorter, J. Arginine-rich dipeptide-repeat proteins as phase disruptors in C9-ALS/FTD. Emerg. Top. Life Sci. 4, 293–305 (2020).
Mackenzie, I. R. A. et al. Quantitative analysis and clinico-pathological correlations of different dipeptide repeat protein pathologies in C9ORF72 mutation carriers. Acta Neuropathol. 130, 845–861 (2015).
Davidson, Y. S. et al. Brain distribution of dipeptide repeat proteins in frontotemporal lobar degeneration and motor neurone disease associated with expansions in C9ORF72. Acta Neuropathol. Commun. 2, 70 (2014).
Davidson, Y. et al. Neurodegeneration in frontotemporal lobar degeneration and motor neurone disease associated with expansions in C9orf72 is linked to TDP-43 pathology and not associated with aggregated forms of dipeptide repeat proteins. Neuropathol. Appl. Neurobiol. 42, 242–254 (2016).
Quaegebeur, A., Glaria, I., Lashley, T. & Isaacs, A. M. Soluble and insoluble dipeptide repeat protein measurements in C9orf72-frontotemporal dementia brains show regional differential solubility and correlation of poly-GR with clinical severity. Acta Neuropathol. Commun. 8, 184 (2020).
Goodman, L. D. et al. eIF4B and eIF4H mediate GR production from expanded G4C2 in a Drosophila model for C9orf72-associated ALS. Acta Neuropathol. Commun. 7, 62 (2019).
Ayhan, F. et al. SCA8 RAN polySer protein preferentially accumulates in white matter regions and is regulated by eIF3F. EMBO J. 37, e99023 (2018).
Cheng, W. et al. CRISPR-Cas9 screens identify the RNA helicase DDX3X as a repressor of C9ORF72 (GGGGCC)n repeat-associated non-AUG translation. Neuron 104, 885–898.e8 (2019).
Harding, H. P. et al. An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol. Cell 11, 619–633 (2003).
Pakos-Zebrucka, K. et al. The integrated stress response. EMBO Rep. 17, 1374–1395 (2016).
Harding, H. P. et al. Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol. Cell 6, 1099–1108 (2000).
Zu, T. et al. Metformin inhibits RAN translation through PKR pathway and mitigates disease in C9orf72 ALS/FTD mice. Proc. Natl Acad. Sci. USA 117, 18591–18599 (2020).
Tiscornia, G. & Mahadevan, M. S. Myotonic dystrophy: the role of the CUG triplet repeats in splicing of a novel DMPK exon and altered cytoplasmic DMPK mRNA isoform ratios. Mol. Cell 5, 959–967 (2000).
Sznajder, Ł. J. et al. Intron retention induced by microsatellite expansions as a disease biomarker. Proc. Natl Acad. Sci. USA 115, 4234–4239 (2018).
Sirp, A. et al. The Fuchs corneal dystrophy-associated CTG repeat expansion in the TCF4 gene affects transcription from its alternative promoters. Sci. Rep. 10, 18424 (2020).
Sareen, D. et al. Targeting RNA foci in iPSC-derived motor neurons from ALS patients with a C9ORF72 repeat expansion. Sci. Transl. Med. 5, 208ra149 (2013).
Neueder, A. et al. The pathogenic exon 1 HTT protein is produced by incomplete splicing in Huntington’s disease patients. Sci. Rep. 7, 1307 (2017).
Shi, Y. et al. Haploinsufficiency leads to neurodegeneration in C9ORF72 ALS/FTD human induced motor neurons. Nat. Med. 24, 313–325 (2018).
Shao, Q. et al. C9orf72 deficiency promotes motor deficits of a C9ALS/FTD mouse model in a dose-dependent manner. Acta Neuropathol. Commun. 7, 32 (2019).
Zhu, Q. et al. Reduced C9ORF72 function exacerbates gain of toxicity from ALS/FTD-causing repeat expansion in C9orf72. Nat. Neurosci. 23, 615–624 (2020).
Gray, M. et al. Full-length human mutant huntingtin with a stable polyglutamine repeat can elicit progressive and selective neuropathogenesis in BACHD mice. J. Neurosci. Off. J. Soc. Neurosci. 28, 6182–6195 (2008).
Li, L.-B., Yu, Z., Teng, X. & Bonini, N. M. RNA toxicity is a component of ataxin-3 degeneration in Drosophila. Nature 453, 1107–1111 (2008).
Rué, L. et al. Targeting CAG repeat RNAs reduces Huntington’s disease phenotype independently of huntingtin levels. J. Clin. Invest. 126, 4319–4330 (2016).
Wang, Q., Conlon, E. G., Manley, J. L. & Rio, D. C. Widespread intron retention impairs protein homeostasis in C9orf72 ALS brains. Genome Res. 30, 1705–1715 (2020).
Hautbergue, G. M. et al. SRSF1-dependent nuclear export inhibition of C9ORF72 repeat transcripts prevents neurodegeneration and associated motor deficits. Nat. Commun. 8, 16063 (2017).
Cleary, J. D., Pattamatta, A. & Ranum, L. P. W. Repeat-associated non-ATG (RAN) translation. J. Biol. Chem. 293, 16127–16141 (2018).
McEachin, Z. T. et al. Chimeric peptide species contribute to divergent dipeptide repeat pathology in c9ALS/FTD and SCA36. Neuron 107, 292–305.e6 (2020).
Toulouse, A. et al. Ribosomal frameshifting on MJD-1 transcripts with long CAG tracts. Hum. Mol. Genet. 14, 2649–2660 (2005).
Wills, N. M. & Atkins, J. F. The potential role of ribosomal frameshifting in generating aberrant proteins implicated in neurodegenerative diseases. RNA 12, 1149–1153 (2006).
Stochmanski, S. J. et al. Expanded ATXN3 frameshifting events are toxic in Drosophila and mammalian neuron models. Hum. Mol. Genet. 21, 2211–2218 (2012).
Saffert, P., Adamla, F., Schieweck, R., Atkins, J. F. & Ignatova, Z. An expanded CAG repeat in huntingtin causes +1 frameshifting. J. Biol. Chem. 291, 18505–18513 (2016).
Ma, L. et al. Composition of the intranuclear inclusions of fragile X-associated tremor/ataxia syndrome. Acta Neuropathol. Commun. 7, 143 (2019).
Haify, S. N. et al. Lack of a clear behavioral phenotype in an inducible FXTAS mouse model despite the presence of neuronal FMRpolyG-positive aggregates. Front. Mol. Biosci. 7, 599101 (2020).
Asamitsu, S. et al. CGG repeat RNA G-quadruplexes interact with FMRpolyG to cause neuronal dysfunction in fragile X-related tremor/ataxia syndrome. Sci. Adv. 7, eabd9440 (2021).
Heatwole, C. et al. Patient-reported impact of symptoms in myotonic dystrophy type 1 (PRISM-1). Neurology 79, 348 (2012).
Ashizawa, T., Dubel, J. R. & Harati, Y. Somatic instability of CTG repeat in myotonic dystrophy. Neurology 43, 2674–2678 (1993).
Sznajder, Ł. J. et al. Loss of MBNL1 induces RNA misprocessing in the thymus and peripheral blood. Nat. Commun. 11, 2022 (2020).
Ishiura, H. et al. Expansions of intronic TTTCA and TTTTA repeats in benign adult familial myoclonic epilepsy. Nat. Genet. 50, 581–590 (2018).
Corbett, M. A. et al. Intronic ATTTC repeat expansions in STARD7 in familial adult myoclonic epilepsy linked to chromosome 2. Nat. Commun. 10, 4920 (2019).
Florian, R. T. et al. Unstable TTTTA/TTTCA expansions in MARCH6 are associated with familial adult myoclonic epilepsy type 3. Nat. Commun. 10, 4919 (2019).
Yeetong, P. et al. TTTCA repeat insertions in an intron of YEATS2 in benign adult familial myoclonic epilepsy type 4. Brain J. Neurol. 142, 3360–3366 (2019).
Seixas, A. I. et al. A pentanucleotide ATTTC repeat insertion in the non-coding region of DAB1, mapping to SCA37, causes spinocerebellar ataxia. Am. J. Hum. Genet. 101, 87–103 (2017).
Saudou, F. & Humbert, S. The biology of huntingtin. Neuron 89, 910–926 (2016).
Rüb, U. et al. Degeneration of the cerebellum in Huntington’s disease (HD): possible relevance for the clinical picture and potential gateway to pathological mechanisms of the disease process. Brain Pathol. 23, 165–177 (2013).
Shortt, J. A., Ruggiero, R. P., Cox, C., Wacholder, A. C. & Pollock, D. D. Finding and extending ancient simple sequence repeat-derived regions in the human genome. Mob. DNA 11, 11 (2020).
Pheasant, M. & Mattick, J. S. Raising the estimate of functional human sequences. Genome Res. 17, 1245–1253 (2007).
Elden, A. C. et al. Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. Nature 466, 1069–1075 (2010). Ataxin 2 can modify TDP43 toxicity in yeast and flies, and intermediate repeats in ataxinК2 serve as a common risk allele in ALS.
Tazelaar, G. H. P. et al. ATXN1 repeat expansions confer risk for amyotrophic lateral sclerosis and contribute to TDP-43 mislocalization. Brain Commun. 2, fcaa064 (2020).
Conforti, F. L. et al. Ataxin-1 and ataxin-2 intermediate-length polyQ expansions in amyotrophic lateral sclerosis. Neurology 79, 2315–2320 (2012).
Lattante, S. et al. ATXN1 intermediate-length polyglutamine expansions are associated with amyotrophic lateral sclerosis. Neurobiol. Aging 64, 157.e1–157.e5 (2018).
R, D. et al. Pathogenic huntingtin repeat expansions in patients with frontotemporal dementia and amyotrophic lateral sclerosis. Neuron 109, 448–460 (2021).
Blauw, H. M. et al. NIPA1 polyalanine repeat expansions are associated with amyotrophic lateral sclerosis. Hum. Mol. Genet. 21, 2497–2502 (2012).
Course, M. M. et al. Evolution of a human-specific tandem repeat associated with ALS. Am. J. Hum. Genet. 107, 445–460 (2020).
Yuan, Y. et al. Identification of GGC repeat expansion in the NOTCH2NLC gene in amyotrophic lateral sclerosis. Neurology 95, e3394–e3405 (2020).
Willems, T. et al. Genome-wide profiling of heritable and de novo STR variations. Nat. Methods 14, 590–592 (2017).
Trost, B. et al. Genome-wide detection of tandem DNA repeats that are expanded in autism. Nature 586, 80–86 (2020). Repeat expansions are a common feature in autism genomes and occur at a much higher frequency than previously appreciated.
Mitra, I. et al. Patterns of de novo tandem repeat mutations and their role in autism. Nature 589, 246–250 (2021).
Jansen, A., Gemayel, R. & Verstrepen, K. J. Unstable microsatellite repeats facilitate rapid evolution of coding and regulatory sequences. Genome Dyn. 7, 108–125 (2012).
Vinces, M. D., Legendre, M., Caldara, M., Hagihara, M. & Verstrepen, K. J. Unstable tandem repeats in promoters confer transcriptional evolvability. Science 324, 1213–1216 (2009).
Verstrepen, K. J., Jansen, A., Lewitter, F. & Fink, G. R. Intragenic tandem repeats generate functional variability. Nat. Genet. 37, 986–990 (2005).
Caron, N. S., Desmond, C. R., Xia, J. & Truant, R. Polyglutamine domain flexibility mediates the proximity between flanking sequences in huntingtin. Proc. Natl. Acad. Sci. USA 110, 14610–14615 (2013).
Ashkenazi, A. et al. Polyglutamine tracts regulate beclin 1-dependent autophagy. Nature 545, 108–111 (2017).
Liquori, C. L. et al. Myotonic dystrophy type 2 caused by a CCTG expansion in intron 1 of ZNF9. Science 293, 864–867 (2001).
Ranum, L. P. W. & Day, J. W. Myotonic dystrophy: clinical and molecular parallels between myotonic dystrophy type 1 and type 2. Curr. Neurol. Neurosci. Rep. 2, 465–470 (2002).
Kim, G., Gautier, O., Tassoni-Tsuchida, E., Ma, X. R. & Gitler, A. D. ALS genetics: gains, losses, and implications for future therapies. Neuron 108, 822–842 (2020).
Ishiura, H. et al. Noncoding CGG repeat expansions in neuronal intranuclear inclusion disease, oculopharyngodistal myopathy and an overlapping disease. Nat. Genet. 51, 1222–1232 (2019).
Sone, J. et al. Long-read sequencing identifies GGC repeat expansions in NOTCH2NLC associated with neuronal intranuclear inclusion disease. Nat. Genet. 51, 1215–1221 (2019).
Tian, Y. et al. Expansion of human-specific GGC repeat in neuronal intranuclear inclusion disease-related disorders. Am. J. Hum. Genet. 105, 166–176 (2019).
Gelpi, E. et al. Neuronal intranuclear (hyaline) inclusion disease and fragile X-associated tremor/ataxia syndrome: a morphological and molecular dilemma. Brain J. Neurol. 140, e51 (2017).
Boivin, M. et al. Translation of GGC repeat expansions into a toxic polyglycine protein in NIID defines a novel class of human genetic disorders: the polyG diseases. Neuron https://doi.org/10.1016/j.neuron.2021.03.038 (2021).
Cortese, A. et al. Biallelic expansion of an intronic repeat in RFC1 is a common cause of late-onset ataxia. Nat. Genet. 51, 649–658 (2019). A new recessively inherited repeat expansion, whose generation and pathogenesis mechanisms remain a mystery, is discovered.
Rafehi, H. et al. Bioinformatics-based identification of expanded repeats: a non-reference intronic pentamer expansion in RFC1 causes CANVAS. Am. J. Hum. Genet. 105, 151–165 (2019).
Scriba, C. K. et al. A novel RFC1 repeat motif (ACAGG) in two Asia-Pacific CANVAS families. Brain J. Neurol. 143, 2904–2910 (2020).
Tsuchiya, M. et al. RFC1 repeat expansion in Japanese patients with late-onset cerebellar ataxia. J. Hum. Genet. 65, 1143–1147 (2020).
Beecroft, S. J. et al. A Māori specific RFC1 pathogenic repeat configuration in CANVAS, likely due to a founder allele. Brain J. Neurol. 143, 2673–2680 (2020).
Jones, C. et al. Association of a chromosome deletion syndrome with a fragile site within the proto-oncogene CBL2. Nature 376, 145–149 (1995).
Parodi, S. et al. Parental origin and somatic mosaicism of PHOX2B mutations in congenital central hypoventilation syndrome. Hum. Mutat. 29, 206–206 (2008).
Owens, K. M. et al. Analysis of de novo HOXA13 polyalanine expansions supports replication slippage without repair in their generation. Am. J. Med. Genet. A. 161, 1019–1027 (2013).
Brown, L. Y. et al. Holoprosencephaly due to mutations in ZIC2: alanine tract expansion mutations may be caused by parental somatic recombination. Hum. Mol. Genet. 10, 791–796 (2001).
Poirier, K. et al. Maternal mosaicism for mutations in the ARX gene in a family with X linked mental retardation. Hum. Genet. 118, 45–48 (2005).
Friocourt, G. & Parnavelas, J. G. Mutations in ARX result in several defects involving GABAergic neurons. Front. Cell. Neurosci. 4, (2010).
This work was supported by US National Institutes of Health grants NS099280, NS086810 and P50HD104463 and VA grant BLRD BX004842 to P.K.T., and US National Institutes of Health grants AG058636, R01NS112291 and R01NS114253 to E.T.W. I.M. was supported by the Alzheimer’s Association Research Fellowship (AARF-20-684648). C.P.K. is supported by the US National Science Foundation Graduate Research Fellowship Program.
P.K.T. holds a shared patent with Ionis Pharmaceuticals on ASO technologies for use against RAN translation. He also serves as a paid consultant for Denali Therapeutics, holds stock options in this company and has received licensing fees for use of experimental tools developed by his research group. The other authors declare no competing interests.
Peer review information
Nature Reviews Molecular Cell Biology thanks Clotilde Lagier-Tourenne and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
- Non-canonical translation
Translation initiation that does not require one or more canonical RNA features, such as a 5′ cap or an AUG start codon.
- Somatic instability
DNA repair-mediated differences in the number of short tandem repeats between cells of an individual which develop over their lifetime.
(RNP). A transient or stable complex formed by multivalent interaction of proteins and RNAs.
- Repeat-associated non-AUG (RAN) translation
A form of non-canonical translation initiated at an expanded-repeat RNA in the absence of an AUG start codon.
- Transcriptional gene silencing
The process of inhibiting RNA polymerase-mediated RNA synthesis, which results in abolition of or partial decrease in RNA production.
A three-stranded RNA–DNA hybrid structure containing two strands of DNA and one strand of RNA, the latter of which forms Watson–Crick base pairs with the complementary DNA strand.
- Rare fragile site
Refers to rare heritable expanded repeat loci that tend to break when cells are exposed to replication stress, such as growth in a folate-free medium.
- DNA mismatch repair
(MMR). Repair pathway of erroneous insertions, deletions and base misincorporations during DNA replication and transcription. MMR has a role in resolving R-loops and repairing DNA damage caused by oxidative stress.
- RNA foci
RNA clusters formed by accumulation of expanded-repeat RNAs or ribonucleoprotein complexes, primarily in the nucleus and sometimes in the cytoplasm.
- Secondary structures
The patterns of intramolecular base pairing of nucleotides within an RNA molecule.
Stable nucleic acid secondary structures formed by the stacking of several planar guanine quadruplets.
- A-form double helix
A right-handed, compact helical structure formed by RNA–DNA and RNA–RNA duplexes.
- Phase separation
The thermodynamic process by which a homogeneous mixture of components separates spontaneously into different coexisting phases. In aqueous solutions of biomolecules, phase separation is often driven by intrinsically disordered proteins and/or multivalent interactions between proteins and RNAs.
- Phase diagram
A graphical depiction of the phases accessible to a system as a function of multiple thermodynamic properties.
- Near-cognate start codons
Also known as near-AUG codons, these codons differ from the canonical AUG start codon by a single base, for example, a CUG codon.
- Upstream open reading frames
(uORFs). Small open reading frames in the 5′ untranslated region of an mRNA capable of undergoing translation.
- Internal ribosomal entry site
(IRES). A structured RNA element that allows non-canonical translation initiation from within the mRNA without requiring a 5′ cap.
- Stress granules
Membraneless ribonucleoprotein compartments that appear in the cytosol in response to various cellular stresses.
Shifts or slips of translating ribosomes along the mRNA which change the open reading frame and the sequence of the translated protein.
About this article
Cite this article
Malik, I., Kelley, C.P., Wang, E.T. et al. Molecular mechanisms underlying nucleotide repeat expansion disorders. Nat Rev Mol Cell Biol (2021). https://doi.org/10.1038/s41580-021-00382-6