Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Molecular genetics of myotonic dystrophy and the evolution of therapeutic approaches

Journal of Human Genetics (2025)Cite this article

Subjects

Abstract

Myotonic dystrophy (DM) is the most common form of adult-onset muscular dystrophy, characterized by skeletal muscle symptoms such as myotonia and progressive muscle wasting, alongside a wide array of multisystemic manifestations affecting the cardiovascular, gastrointestinal, central nervous, endocrine, and ocular systems. DM is an autosomal dominant disorder caused by the unstable expansion of non-coding repeat sequences within the disease-causative genes. The mutant transcripts harboring these expanded repeats exert pathogenic effects via a toxic gain-of-function mechanism, most notably through RNA mediated toxicity that perturbs alternative splicing regulation and contributes to the diverse clinical phenotype. Beyond splicing defects, aberrant signal transduction and the activation of cellular senescence pathways have also been implicated in disease pathophysiology. This review summarizes current understanding of the molecular genetics and mechanistic basis of DM, outlines recent progress in therapeutic development—particularly RNA-targeted strategies involving nucleic acid-based therapeutics and small molecules—and explores emerging approaches aimed at modulating repeat expansions as a means to mitigate disease progression.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1

Similar content being viewed by others

References

  1. Nakamori, M & Takahashi, MP Myotonic dystrophy. In: Takeda S, Miyagoe-Suzuki Y, Mori-Yoshimura M, editors. Translational research in muscular dystrophy. Tokyo: Springer Japan; 2016. p. 39–61.

  2. Johnson NE, Butterfield RJ, Mayne K, Newcomb T, Imburgia C, Dunn D, et al. Population Based Prevalence of Myotonic Dystrophy Type 1 Using Genetic Analysis of State-wide Blood Screening Program. Neurology. 2021;96:e1045–e1053.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Ibanez K, Jadhav B, Zanovello M, Gagliardi D, Clarkson C, Facchini S, et al. Increased frequency of repeat expansion mutations across different populations. Nat Med. 2024;30:3357–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Wenninger S, Montagnese F, Schoser B. Core Clinical Phenotypes in Myotonic Dystrophies. Front Neurol. 2018;9:303.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Wahbi K, Babuty D, Probst V, Wissocque L, Labombarda F, Porcher R, et al. Incidence and predictors of sudden death, major conduction defects and sustained ventricular tachyarrhythmias in 1388 patients with myotonic dystrophy type 1. Eur Heart J. 2017;38:751–58.

    PubMed  Google Scholar 

  6. White M. Patient Input to Inform the Development of Central Nervous System Outcome Measures in Myotonic Dystrophy. Ther Innov Regul Sci. 2020;54:1010–17.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Peric S, Ivanovic V, Ashley EJ, Esparis B, Campbell C, Wenninger S, et al. International collaboration to improve knowledge on myotonic dystrophy type 2. J Neuromuscul Dis. 2024;11:1229–37.

    Article  PubMed  Google Scholar 

  8. Liao Q, Zhang Y, He J, Huang K. Global Prevalence of Myotonic Dystrophy: An Updated Systematic Review and Meta-Analysis. Neuroepidemiology. 2022;56:163–73.

    Article  PubMed  Google Scholar 

  9. Wenninger S, Cumming SA, Gutschmidt K, Okkersen K, Jimenez-Moreno AC, Daidj F, et al. Associations Between Variant Repeat Interruptions and Clinical Outcomes in Myotonic Dystrophy Type 1. Neurol Genet. 2021;7:e572.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Lopez Castel A, Nakamori M, Tome S, Chitayat D, Gourdon G, Thornton CA, et al. Expanded CTG repeat demarcates a boundary for abnormal CpG methylation in myotonic dystrophy patient tissues. Hum Mol Genet. 2011;20:1–15.

    Article  PubMed  Google Scholar 

  11. Nakamori M, Hamanaka K, Thomas JD, Wang ET, Hayashi YK, Takahashi MP, et al. Aberrant Myokine Signaling in Congenital Myotonic Dystrophy. Cell Rep. 2017;21:1240–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ashizawa T, Anvret M, Baiget M, Barcelo JM, Brunner H, Cobo AM, et al. Characteristics of intergenerational contractions of the CTG repeat in myotonic dystrophy. Am J Hum Genet. 1994;54:414–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Lagrue E, Dogan C, De Antonio M, Audic F, Bach N, Barnerias C, et al. A large multicenter study of pediatric myotonic dystrophy type 1 for evidence-based management. Neurology. 2019;92:e852–e65.

    Article  PubMed  Google Scholar 

  14. Nakamori M, Sobczak K, Moxley RT 3rd, Thornton CA. Scaled-down genetic analysis of myotonic dystrophy type 1 and type 2. Neuromuscul Disord. 2009;19:759–62.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Nakamori M, Shimizu H, Ogawa K, Hasuike Y, Nakajima T, Sakurai H, et al. Cell type-specific abnormalities of central nervous system in myotonic dystrophy type 1. Brain Commun. 2022;4:fcac154.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Schmidt MHM, Pearson CE. Disease-associated repeat instability and mismatch repair. DNA Repair (Amst). 2016;38:117–26.

    Article  CAS  PubMed  Google Scholar 

  17. Nakamori M, Gourdon G, Thornton CA. Stabilization of expanded (CTG)*(CAG) repeats by antisense oligonucleotides. Mol Ther. 2011;19:2222–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Lee KY, Li M, Manchanda M, Batra R, Charizanis K, Mohan A, et al. Compound loss of muscleblind-like function in myotonic dystrophy. EMBO Mol Med. 2013;5:1887–900.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Koshelev M, Sarma S, Price RE, Wehrens XH, Cooper TA. Heart-specific overexpression of CUGBP1 reproduces functional and molecular abnormalities of myotonic dystrophy type 1. Hum Mol Genet. 2010;19:1066–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Mankodi A, Takahashi MP, Jiang H, Beck CL, Bowers WJ, Moxley RT, et al. Expanded CUG repeats trigger aberrant splicing of ClC-1 chloride channel pre-mRNA and hyperexcitability of skeletal muscle in myotonic dystrophy. Mol Cell. 2002;10:35–44.

    Article  CAS  PubMed  Google Scholar 

  21. Savkur RS, Philips AV, Cooper TA. Aberrant regulation of insulin receptor alternative splicing is associated with insulin resistance in myotonic dystrophy. Nat Genet. 2001;29:40–7.

    Article  CAS  PubMed  Google Scholar 

  22. Freyermuth F, Rau F, Kokunai Y, Linke T, Sellier C, Nakamori M, et al. Splicing misregulation of SCN5A contributes to cardiac-conduction delay and heart arrhythmia in myotonic dystrophy. Nat Commun. 2016;7:11067.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kimura T, Nakamori M, Lueck JD, Pouliquin P, Aoike F, Fujimura H, et al. Altered mRNA splicing of the skeletal muscle ryanodine receptor and sarcoplasmic/endoplasmic reticulum Ca2+-ATPase in myotonic dystrophy type 1. Hum Mol Genet. 2005;14:2189–200.

    Article  CAS  PubMed  Google Scholar 

  24. Tang ZZ, Yarotskyy V, Wei L, Sobczak K, Nakamori M, Eichinger K, et al. Muscle weakness in myotonic dystrophy associated with misregulated splicing and altered gating of Ca(V)1.1 calcium channel. Hum Mol Genet. 2012;21:1312–24.

    Article  CAS  PubMed  Google Scholar 

  25. Fugier C, Klein AF, Hammer C, Vassilopoulos S, Ivarsson Y, Toussaint A, et al. Misregulated alternative splicing of BIN1 is associated with T tubule alterations and muscle weakness in myotonic dystrophy. Nat Med. 2011;17:720–5.

    Article  CAS  PubMed  Google Scholar 

  26. Nakamori M, Kimura T, Fujimura H, Takahashi MP, Sakoda S. Altered mRNA splicing of dystrophin in type 1 myotonic dystrophy. Muscle Nerve. 2007;36:251–7.

    Article  CAS  PubMed  Google Scholar 

  27. Nakamori M, Kimura T, Kubota T, Matsumura T, Sumi H, Fujimura H, et al. Aberrantly spliced alpha-dystrobrevin alters alpha-syntrophin binding in myotonic dystrophy type 1. Neurology. 2008;70:677–85.

    Article  CAS  PubMed  Google Scholar 

  28. Nakamori M, Sobczak K, Puwanant A, Welle S, Eichinger K, Pandya S, et al. Splicing biomarkers of disease severity in myotonic dystrophy. Ann Neurol. 2013;74:862–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Provenzano M, Ikegami K, Bates K, Gaynor A, Hartman JM, Jones A, et al. The Splice Index as a prognostic biomarker of strength and function in myotonic dystrophy type 1. J Clin Invest. 2025;135:e185426.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Sergeant N, Sablonniere B, Schraen-Maschke S, Ghestem A, Maurage CA, Wattez A, et al. Dysregulation of human brain microtubule-associated tau mRNA maturation in myotonic dystrophy type 1. Hum Mol Genet. 2001;10:2143–55.

    Article  CAS  PubMed  Google Scholar 

  31. Jiang H, Mankodi A, Swanson MS, Moxley RT, Thornton CA. Myotonic dystrophy type 1 is associated with nuclear foci of mutant RNA, sequestration of muscleblind proteins and deregulated alternative splicing in neurons. Hum Mol Genet. 2004;13:3079–88.

    Article  CAS  PubMed  Google Scholar 

  32. Suenaga K, Lee KY, Nakamori M, Tatsumi Y, Takahashi MP, Fujimura H, et al. Muscleblind-like 1 knockout mice reveal novel splicing defects in the myotonic dystrophy brain. PLoS One. 2012;7:e33218.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Furuta M, Kimura T, Nakamori M, Matsumura T, Fujimura H, Jinnai K, et al. Macroscopic and microscopic diversity of missplicing in the central nervous system of patients with myotonic dystrophy type 1. Neuroreport. 2018;29:235–40.

    Article  PubMed  Google Scholar 

  34. Sznajder LJ, Khan M, Ciesiolka A, Tadross M, Nutter CA, Taylor K, et al. Autism-related traits in myotonic dystrophy type 1 model mice are due to MBNL sequestration and RNA mis-splicing of autism-risk genes. Nat Neurosci. 2025. https://doi.org/10.1038/s41593-025-01943-0.

  35. Auxerre-Plantie E, Nakamori M, Renaud Y, Huguet A, Choquet C, Dondi C, et al. Straightjacket/alpha2delta3 deregulation is associated with cardiac conduction defects in myotonic dystrophy type 1. Elife. 2019;8:e51114.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Rau F, Freyermuth F, Fugier C, Villemin JP, Fischer MC, Jost B, et al. Misregulation of miR-1 processing is associated with heart defects in myotonic dystrophy. Nat Struct Mol Biol. 2011;18:840–5.

    Article  CAS  PubMed  Google Scholar 

  37. Souidi A, Nakamori M, Zmojdzian M, Jagla T, Renaud Y, Jagla K. Deregulations of miR-1 and its target Multiplexin promote dilated cardiomyopathy associated with myotonic dystrophy type 1. EMBO Rep. 2023;24. e56616.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Wang ET, Cody NA, Jog S, Biancolella M, Wang TT, Treacy DJ, et al. Transcriptome-wide regulation of pre-mRNA splicing and mRNA localization by muscleblind proteins. Cell. 2012;150:710–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Batra R, Charizanis K, Manchanda M, Mohan A, Li M, Finn DJ, et al. Loss of MBNL leads to disruption of developmentally regulated alternative polyadenylation in RNA-mediated disease. Mol Cell. 2014;56:311–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Vlasova IA, Tahoe NM, Fan D, Larsson O, Rattenbacher B, Sternjohn JR, et al. Conserved GU-rich elements mediate mRNA decay by binding to CUG-binding protein 1. Mol Cell. 2008;29:263–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Huichalaf C, Sakai K, Jin B, Jones K, Wang GL, Schoser B, et al. Expansion of CUG RNA repeats causes stress and inhibition of translation in myotonic dystrophy 1 (DM1) cells. FASEB J. 2010;24:3706–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Sellier C, Cerro-Herreros E, Blatter M, Freyermuth F, Gaucherot A, Ruffenach F, et al. rbFOX1/MBNL1 competition for CCUG RNA repeats binding contributes to myotonic dystrophy type 1/type 2 differences. Nat Commun. 2018;9:2009.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Misra C, Bangru S, Lin F, Lam K, Koenig SN, Lubbers ER, et al. Aberrant Expression of a Non-muscle RBFOX2 Isoform Triggers Cardiac Conduction Defects in Myotonic Dystrophy. Dev Cell. 2020;52:748–63.e6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Crawford Parks TE, Marcellus KA, Peladeau C, Jasmin BJ, Ravel-Chapuis A. Overexpression of Staufen1 in DM1 mouse skeletal muscle exacerbates dystrophic and atrophic features. Hum Mol Genet. 2020;29:2185–99.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Zu T, Gibbens B, Doty NS, Gomes-Pereira M, Huguet A, Stone MD, et al. Non-ATG-initiated translation directed by microsatellite expansions. Proc Natl Acad Sci USA. 2011;108:260–5.

    Article  CAS  PubMed  Google Scholar 

  46. Guo S, Nguyen L, Ranum LPW. RAN proteins in neurodegenerative disease: Repeating themes and unifying therapeutic strategies. Curr Opin Neurobiol. 2022;72:160–70.

    Article  CAS  PubMed  Google Scholar 

  47. Zu T, Cleary JD, Liu Y, Banez-Coronel M, Bubenik JL, Ayhan F, et al. RAN Translation Regulated by Muscleblind Proteins in Myotonic Dystrophy Type 2. Neuron. 2017;95:1292–305.e5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Kuyumcu-Martinez NM, Wang GS, Cooper TA. Increased steady-state levels of CUGBP1 in myotonic dystrophy 1 are due to PKC-mediated hyperphosphorylation. Mol Cell. 2007;28:68–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Jones K, Wei C, Iakova P, Bugiardini E, Schneider-Gold C, Meola G, et al. GSK3beta mediates muscle pathology in myotonic dystrophy. J Clin Invest. 2012;122:4461–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Salisbury E, Sakai K, Schoser B, Huichalaf C, Schneider-Gold C, Nguyen H, et al. Ectopic expression of cyclin D3 corrects differentiation of DM1 myoblasts through activation of RNA CUG-binding protein, CUGBP1. Exp Cell Res. 2008;314:2266–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Brockhoff M, Rion N, Chojnowska K, Wiktorowicz T, Eickhorst C, Erne B, et al. Targeting deregulated AMPK/mTORC1 pathways improves muscle function in myotonic dystrophy type I. J Clin Invest. 2017;127:549–63.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Hasuike Y, Mochizuki H, Nakamori M. Cellular Senescence and Aging in Myotonic Dystrophy. Int J Mol Sci. 2022;23:2339.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Furling D, Coiffier L, Mouly V, Barbet JP, St Guily JL, Taneja K, et al. Defective satellite cells in congenital myotonic dystrophy. Hum Mol Genet. 2001;10:2079–87.

    Article  CAS  PubMed  Google Scholar 

  54. Bigot A, Klein AF, Gasnier E, Jacquemin V, Ravassard P, Butler-Browne G, et al. Large CTG repeats trigger p16-dependent premature senescence in myotonic dystrophy type 1 muscle precursor cells. Am J Pathol. 2009;174:1435–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Toscano A, Messina S, Campo GM, Di Leo R, Musumeci O, Rodolico C, et al. Oxidative stress in myotonic dystrophy type 1. Free Radic Res. 2005;39:771–6.

    Article  CAS  PubMed  Google Scholar 

  56. Garcia-Puga M, Saenz-Antonanzas A, Fernandez-Torron R, Munain AL, Matheu A. Myotonic Dystrophy type 1 cells display impaired metabolism and mitochondrial dysfunction that are reversed by metformin. Aging (Albany NY). 2020;12:6260–75.

    Article  CAS  PubMed  Google Scholar 

  57. Hasuike Y, Mochizuki H, Nakamori M. Expanded CUG Repeat RNA Induces Premature Senescence in Myotonic Dystrophy Model Cells. Front Genet. 2022;13:865811.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Garcia-Puga M, Saenz-Antonanzas A, Gerenu G, Arrieta A, Fernandez-Torron R, Zulaica M, et al. Senescence plays a role in Myotonic Dystrophy type 1. JCI Insight. 2022;7:e159357.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Mulders SA, van den Broek WJ, Wheeler TM, Croes HJ, van Kuik-Romeijn P, de Kimpe SJ, et al. Triplet-repeat oligonucleotide-mediated reversal of RNA toxicity in myotonic dystrophy. Proc Natl Acad Sci USA. 2009;106:13915–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Wheeler TM, Leger AJ, Pandey SK, MacLeod AR, Nakamori M, Cheng SH, et al. Targeting nuclear RNA for in vivo correction of myotonic dystrophy. Nature. 2012;488:111–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Pandey SK, Wheeler TM, Justice SL, Kim A, Younis HS, Gattis D, et al. Identification and characterization of modified antisense oligonucleotides targeting DMPK in mice and nonhuman primates for the treatment of myotonic dystrophy type 1. J Pharm Exp Ther. 2015;355:329–40.

    Article  Google Scholar 

  62. Wojtkowiak-Szlachcic A, Taylor K, Stepniak-Konieczna E, Sznajder LJ, Mykowska A, Sroka J, et al. Short antisense-locked nucleic acids (all-LNAs) correct alternative splicing abnormalities in myotonic dystrophy. Nucleic Acids Res. 2015;43:3318–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Klein AF, Varela MA, Arandel L, Holland A, Naouar N, Arzumanov A, et al. Peptide-conjugated oligonucleotides evoke long-lasting myotonic dystrophy correction in patient-derived cells and mice. J Clin Invest. 2019;129:4739–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Thornton CA, Moxley RT 3rd, Eichinger K, Heatwole C, Mignon L, Arnold WD, et al. Antisense oligonucleotide targeting DMPK in patients with myotonic dystrophy type 1: a multicentre, randomised, dose-escalation, placebo-controlled, phase 1/2a trial. Lancet Neurol. 2023;22:218–28.

    Article  CAS  PubMed  Google Scholar 

  65. Weeden T, Picariello T, Quinn B, Spring S, Shen PY, Qiu Q, et al. FORCE platform overcomes barriers of oligonucleotide delivery to muscle and corrects myotonic dystrophy features in preclinical models. Commun Med (Lond). 2025;5:22.

    Article  PubMed  Google Scholar 

  66. Childs-Disney JL, Parkesh R, Nakamori M, Thornton CA, Disney MD. Rational design of bioactive, modularly assembled aminoglycosides targeting the RNA that causes myotonic dystrophy type 1. ACS Chem Biol. 2012;7:1984–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Parkesh R, Childs-Disney JL, Nakamori M, Kumar A, Wang E, Wang T, et al. Design of a bioactive small molecule that targets the myotonic dystrophy type 1 RNA via an RNA motif-ligand database and chemical similarity searching. J Am Chem Soc. 2012;134:4731–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Ofori LO, Hoskins J, Nakamori M, Thornton CA, Miller BL. From dynamic combinatorial ‘hit’ to lead: in vitro and in vivo activity of compounds targeting the pathogenic RNAs that cause myotonic dystrophy. Nucleic Acids Res. 2012;40:6380–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Li J, Nakamori M, Matsumoto J, Murata A, Dohno C, Kiliszek A, et al. A Dimeric 2,9-Diamino-1,10-phenanthroline Derivative Improves Alternative Splicing in Myotonic Dystrophy Type 1 Cell and Mouse Models. Chemistry. 2018;24:18115–22.

    Article  CAS  PubMed  Google Scholar 

  70. Chen G, Masuda A, Konishi H, Ohkawara B, Ito M, Kinoshita M, et al. Phenylbutazone induces expression of MBNL1 and suppresses formation of MBNL1-CUG RNA foci in a mouse model of myotonic dystrophy. Sci Rep. 2016;6:25317.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Matsumoto J, Nakamori M, Okamoto T, Murata A, Dohno C, Nakatani K. The Dimeric Form of 1,3-Diaminoisoquinoline Derivative Rescued the Mis-splicing of Atp2a1 and Clcn1 Genes in Myotonic Dystrophy Type 1 Mouse Model. Chemistry. 2020;26:14305–09.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Herrendorff R, Faleschini MT, Stiefvater A, Erne B, Wiktorowicz T, Kern F, et al. Identification of Plant-derived Alkaloids with Therapeutic Potential for Myotonic Dystrophy Type I. J Biol Chem. 2016;291:17165–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Warf MB, Nakamori M, Matthys CM, Thornton CA, Berglund JA. Pentamidine reverses the splicing defects associated with myotonic dystrophy. Proc Natl Acad Sci USA. 2009;106:18551–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Coonrod LA, Nakamori M, Wang W, Carrell S, Hilton CL, Bodner MJ, et al. Reducing levels of toxic RNA with small molecules. ACS Chem Biol. 2013;8:2528–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Siboni RB, Bodner MJ, Khalifa MM, Docter AG, Choi JY, Nakamori M, et al. Biological Efficacy and Toxicity of Diamidines in Myotonic Dystrophy Type 1 Models. J Med Chem. 2015;58:5770–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Siboni RB, Nakamori M, Wagner SD, Struck AJ, Coonrod LA, Harriott SA, et al. Actinomycin D Specifically Reduces Expanded CUG Repeat RNA in Myotonic Dystrophy Models. Cell Rep. 2015;13:2386–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Reddy K, Jenquin JR, McConnell OL, Cleary JD, Richardson JI, Pinto BS, et al. A CTG repeat-selective chemical screen identifies microtubule inhibitors as selective modulators of toxic CUG RNA levels. Proc Natl Acad Sci USA. 2019;116:20991–1000.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Wang M, Weng WC, Stock L, Lindquist D, Martinez A, Gourdon G, et al. Correction of Glycogen Synthase Kinase 3beta in Myotonic Dystrophy 1 Reduces the Mutant RNA and Improves Postnatal Survival of DMSXL Mice. Mol Cell Biol. 2019;39:e00155-19.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Cisco LA, Sipple MT, Edwards KM, Thornton CA, Lueck JD. Verapamil mitigates chloride and calcium bi-channelopathy in a myotonic dystrophy mouse model. J Clin Invest. 2024;134:e173576.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Heatwole C, Luebbe E, Rosero S, Eichinger K, Martens W, Hilbert J, et al. Mexiletine in Myotonic Dystrophy Type 1: A Randomized, Double-Blind, Placebo-Controlled Trial. Neurology. 2021;96:e228–e40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Bassez G, Audureau E, Hogrel JY, Arrouasse R, Baghdoyan S, Bhugaloo H, et al. Improved mobility with metformin in patients with myotonic dystrophy type 1: a randomized controlled trial. Brain. 2018;141:2855–65.

    Article  PubMed  Google Scholar 

  82. Horrigan J, Gomes TB, Snape M, Nikolenko N, McMorn A, Evans S, et al. A Phase 2 Study of AMO-02 (Tideglusib) in Congenital and Childhood-Onset Myotonic Dystrophy Type 1 (DM1). Pediatr Neurol. 2020;112:84–93.

    Article  PubMed  Google Scholar 

  83. Nakamori M, Nakatani D, Sato T, Hasuike Y, Kon S, Saito T, et al. Erythromycin for myotonic dystrophy type 1: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. EClinicalMedicine. 2024;67:102390.

    Article  PubMed  Google Scholar 

  84. Arandel L, Matloka M, Klein AF, Rau F, Sureau A, Ney M, et al. Reversal of RNA toxicity in myotonic dystrophy via a decoy RNA-binding protein with high affinity for expanded CUG repeats. Nat Biomed Eng. 2022;6:207–20.

    Article  CAS  PubMed  Google Scholar 

  85. Imai T, Miyai M, Nemoto J, Tamai T, Ohta M, Yagi Y, et al. Pentatricopeptide repeat protein targeting CUG repeat RNA ameliorates RNA toxicity in a myotonic dystrophy type 1 mouse model. Sci Transl Med. 2025;17:eadq2005.

    Article  CAS  PubMed  Google Scholar 

  86. Kanadia RN, Shin J, Yuan Y, Beattie SG, Wheeler TM, Thornton CA, 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. 2006;103:11748–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Hu RC, Zhang Y, Nitschke L, Johnson SJ, Hurley AE, Lagor WR, et al. MBNL overexpression rescues cardiac phenotypes in a myotonic dystrophy type 1 heart mouse model. J Clin Invest. 2025;135:e186416.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Cerro-Herreros E, Sabater-Arcis M, Fernandez-Costa JM, Moreno N, Perez-Alonso M, Llamusi B, et al. miR-23b and miR-218 silencing increase Muscleblind-like expression and alleviate myotonic dystrophy phenotypes in mammalian models. Nat Commun. 2018;9:2482.

    Article  PubMed  PubMed Central  Google Scholar 

  89. Gonzalez-Martinez I, Cerro-Herreros E, Moreno N, Garcia-Rey A, Espinosa-Espinosa J, Carrascosa-Saez M, et al. Peptide-conjugated antimiRs improve myotonic dystrophy type 1 phenotypes by promoting endogenous MBNL1 expression. Mol Ther Nucleic Acids. 2023;34:102024.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Lo Scrudato M, Poulard K, Sourd C, Tome S, Klein AF, Corre G, et al. Genome Editing of Expanded CTG Repeats within the Human DMPK Gene Reduces Nuclear RNA Foci in the Muscle of DM1 Mice. Mol Ther. 2019;27:1372–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Cardinali B, Provenzano C, Izzo M, Voellenkle C, Battistini J, Strimpakos G, et al. Time-controlled and muscle-specific CRISPR/Cas9-mediated deletion of CTG-repeat expansion in the DMPK gene. Mol Ther Nucleic Acids. 2022;27:184–99.

    Article  CAS  PubMed  Google Scholar 

  92. Pinto BS, Saxena T, Oliveira R, Mendez-Gomez HR, Cleary JD, Denes LT, et al. Impeding Transcription of Expanded Microsatellite Repeats by Deactivated Cas9. Mol Cell. 2017;68:479–90 e5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Batra R, Nelles DA, Roth DM, Krach F, Nutter CA, Tadokoro T, et al. The sustained expression of Cas9 targeting toxic RNAs reverses disease phenotypes in mouse models of myotonic dystrophy type 1. Nat Biomed Eng. 2021;5:157–68.

    Article  CAS  PubMed  Google Scholar 

  94. Nakamori M, Panigrahi GB, Lanni S, Gall-Duncan T, Hayakawa H, Tanaka H, et al. A slipped-CAG DNA-binding small molecule induces trinucleotide-repeat contractions in vivo. Nat Genet. 2020;52:146–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Hasuike Y, Tanaka H, Gall-Duncan T, Mehkary M, Nakatani K, Pearson CE, et al. CAG repeat-binding small molecule improves motor coordination impairment in a mouse model of Dentatorubral-pallidoluysian atrophy. Neurobiol Dis. 2022;163:105604.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by Grant-in-Aid for Scientific Research (B) from Japan Society for the Promotion of Science (KAKENHI Grant Number 21H02839 to M.N.), and Intramural Research Grant for Neurological and Psychiatric Disorders of National Center of Neurology and Psychiatry (5-6 to M.N.).

Author information

Authors and Affiliations

  1. Department of Neurology, Yamaguchi University Graduate School of Medicine, Ube, Japan

    Joe Nemoto & Masayuki Nakamori

Authors
  1. Joe Nemoto
    View author publications

    Search author on:PubMed Google Scholar

  2. Masayuki Nakamori
    View author publications

    Search author on:PubMed Google Scholar

Corresponding author

Correspondence to Masayuki Nakamori.

Ethics declarations

Competing interests

The author declares no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nemoto, J., Nakamori, M. Molecular genetics of myotonic dystrophy and the evolution of therapeutic approaches. J Hum Genet (2025). https://doi.org/10.1038/s10038-025-01358-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Version of record:

  • DOI: https://doi.org/10.1038/s10038-025-01358-6

Search

Advanced search

Quick links