Molecular Mechanisms of Myotonic Dystrophy: RNA-Mediated Pathogenesis and RNA-Binding Proteins

  • Yoshihiro KinoEmail author
  • Jun-ichi Satoh
  • Shoichi Ishiura


Since the identification of a repeat expansion as a causative mutation of myotonic dystrophy (dystrophia myotonica, DM) type 1 (DM1), several pathomechanisms have been proposed. Among them, an RNA-mediated mechanism is thought to play a central role in the pathogenesis of DM. In both DM1 and DM type 2 (DM2), mutated alleles produce transcripts containing an expanded CUG (DM1) or CCUG (DM2) tract. These aberrant RNAs accumulate in nuclei and form ribonuclear inclusions or nuclear RNA foci, a pathological hallmark of DM. These transcripts sequester muscleblind-like (MBNL) proteins, which regulate alternative splicing and other RNA processing. Loss of function of MBNL proteins in mouse models recapitulates many aspects of DM. In this chapter, the pathomechanisms of DM1 and DM2 are discussed, with an emphasis on the roles of RNA-binding proteins together with recent findings in this field.


RNA foci MBNL proteins CELF proteins Alternative splicing RAN translation RNA gelation 



This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) to Y.K. (16K09683) and by the Dementia Drug Resource Development Center Project (DRC), MEXT Japan (S1511016). This work was also supported in part by an Intramural Research Grant (26-8) for Neurological and Psychiatric Disorders of NCNP, a research grant for Comprehensive Research on Disability Health and Welfare from the Ministry of Health, Labour and Welfare (MHLW; H26-Sinkeikinn-ippan-004) and a Grant-in-Aid from the MHLW of Japan (to S.I.).


  1. 1.
    Brook JD, McCurrach ME, Harley HG, Buckler AJ, Church D, Aburatani H, et al. Molecular basis of myotonic dystrophy: expansion of a trinucleotide (CTG) repeat at the 3′ end of a transcript encoding a protein kinase family member. Cell. 1992;69(2):385.CrossRefGoogle Scholar
  2. 2.
    Fu YH, Pizzuti A, Fenwick RG Jr, King J, Rajnarayan S, Dunne PW, et al. An unstable triplet repeat in a gene related to myotonic muscular dystrophy. Science. 1992;255(5049):1256–8.CrossRefGoogle Scholar
  3. 3.
    Mahadevan M, Tsilfidis C, Sabourin L, Shutler G, Amemiya C, Jansen G, et al. Myotonic dystrophy mutation: an unstable CTG repeat in the 3′ untranslated region of the gene. Science. 1992;255(5049):1253–5.CrossRefGoogle Scholar
  4. 4.
    Yum K, Wang ET, Kalsotra A. Myotonic dystrophy: disease repeat range, penetrance, age of onset, and relationship between repeat size and phenotypes. Curr Opin Genet Dev. 2017;44:30–7. Scholar
  5. 5.
    Berul CI, Maguire CT, Aronovitz MJ, Greenwood J, Miller C, Gehrmann J, et al. DMPK dosage alterations result in atrioventricular conduction abnormalities in a mouse myotonic dystrophy model. J Clin Invest. 1999;103(4):R1–7. Scholar
  6. 6.
    Jansen G, Groenen PJ, Bachner D, Jap PH, Coerwinkel M, Oerlemans F, et al. Abnormal myotonic dystrophy protein kinase levels produce only mild myopathy in mice. Nat Genet. 1996;13(3):316–24. Scholar
  7. 7.
    Reddy S, Smith DB, Rich MM, Leferovich JM, Reilly P, Davis BM, et al. Mice lacking the myotonic dystrophy protein kinase develop a late onset progressive myopathy. Nat Genet. 1996;13(3):325–35. Scholar
  8. 8.
    Carrell ST, Carrell EM, Auerbach D, Pandey SK, Bennett CF, Dirksen RT, et al. Dmpk gene deletion or antisense knockdown does not compromise cardiac or skeletal muscle function in mice. Hum Mol Genet. 2016;25(19):4328–38. Scholar
  9. 9.
    Klesert TR, Otten AD, Bird TD, Tapscott SJ. Trinucleotide repeat expansion at the myotonic dystrophy locus reduces expression of DMAHP. Nat Genet. 1997;16(4):402–6. Scholar
  10. 10.
    Thornton CA, Wymer JP, Simmons Z, McClain C, Moxley RT 3rd. Expansion of the myotonic dystrophy CTG repeat reduces expression of the flanking DMAHP gene. Nat Genet. 1997;16(4):407–9. Scholar
  11. 11.
    Sarkar PS, Appukuttan B, Han J, Ito Y, Ai C, Tsai W, et al. Heterozygous loss of Six5 in mice is sufficient to cause ocular cataracts. Nat Genet. 2000;25(1):110–4. Scholar
  12. 12.
    Sarkar PS, Paul S, Han J, Reddy S. Six5 is required for spermatogenic cell survival and spermiogenesis. Hum Mol Genet. 2004;13(14):1421–31. Scholar
  13. 13.
    Taneja KL, McCurrach M, Schalling M, Housman D, Singer RH. Foci of trinucleotide repeat transcripts in nuclei of myotonic dystrophy cells and tissues. J Cell Biol. 1995;128(6):995–1002.CrossRefGoogle Scholar
  14. 14.
    Timchenko LT, Miller JW, Timchenko NA, DeVore DR, Datar KV, Lin L, et al. Identification of a (CUG)n triplet repeat RNA-binding protein and its expression in myotonic dystrophy. Nucleic Acids Res. 1996;24(22):4407–14.CrossRefGoogle Scholar
  15. 15.
    Philips AV, Timchenko LT, Cooper TA. Disruption of splicing regulated by a CUG-binding protein in myotonic dystrophy. Science. 1998;280(5364):737–41.CrossRefGoogle Scholar
  16. 16.
    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(1):40–7. Scholar
  17. 17.
    Charlet BN, Savkur RS, Singh G, Philips AV, Grice EA, Cooper TA. Loss of the muscle-specific chloride channel in type 1 myotonic dystrophy due to misregulated alternative splicing. Mol Cell. 2002;10(1):45–53.CrossRefGoogle Scholar
  18. 18.
    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(1):35–44.CrossRefGoogle Scholar
  19. 19.
    Mankodi A, Logigian E, Callahan L, McClain C, White R, Henderson D, et al. Myotonic dystrophy in transgenic mice expressing an expanded CUG repeat. Science. 2000;289(5485):1769–73.CrossRefGoogle Scholar
  20. 20.
    Seznec H, Agbulut O, Sergeant N, Savouret C, Ghestem A, Tabti N, et al. Mice transgenic for the human myotonic dystrophy region with expanded CTG repeats display muscular and brain abnormalities. Hum Mol Genet. 2001;10(23):2717–26.CrossRefGoogle Scholar
  21. 21.
    Guiraud-Dogan C, Huguet A, Gomes-Pereira M, Brisson E, Bassez G, Junien C, et al. DM1 CTG expansions affect insulin receptor isoforms expression in various tissues of transgenic mice. Biochim Biophys Acta. 2007;1772(11–12):1183–91. Scholar
  22. 22.
    Huguet A, Medja F, Nicole A, Vignaud A, Guiraud-Dogan C, Ferry A, et al. Molecular, physiological, and motor performance defects in DMSXL mice carrying >1,000 CTG repeats from the human DM1 locus. PLoS Genet. 2012;8(11):e1003043. Scholar
  23. 23.
    Wang GS, Kearney DL, De Biasi M, Taffet G, Cooper TA. Elevation of RNA-binding protein CUGBP1 is an early event in an inducible heart-specific mouse model of myotonic dystrophy. J Clin Invest. 2007;117(10):2802–11. Scholar
  24. 24.
    Orengo JP, Chambon P, Metzger D, Mosier DR, Snipes GJ, Cooper TA. Expanded CTG repeats within the DMPK 3′ UTR causes severe skeletal muscle wasting in an inducible mouse model for myotonic dystrophy. Proc Natl Acad Sci U S A. 2008;105(7):2646–51. Scholar
  25. 25.
    Miller JW, Urbinati CR, Teng-Umnuay P, Stenberg MG, Byrne BJ, Thornton CA, et al. Recruitment of human muscleblind proteins to (CUG)(n) expansions associated with myotonic dystrophy. EMBO J. 2000;19(17):4439–48. Scholar
  26. 26.
    Fardaei M, Rogers MT, Thorpe HM, Larkin K, Hamshere MG, Harper PS, et al. Three proteins, MBNL, MBLL and MBXL, co-localize in vivo with nuclear foci of expanded-repeat transcripts in DM1 and DM2 cells. Hum Mol Genet. 2002;11(7):805–14.CrossRefGoogle Scholar
  27. 27.
    Lin X, Miller JW, Mankodi A, Kanadia RN, Yuan Y, Moxley RT, et al. Failure of MBNL1-dependent post-natal splicing transitions in myotonic dystrophy. Hum Mol Genet. 2006;15(13):2087–97. Scholar
  28. 28.
    Ho TH, Charlet BN, Poulos MG, Singh G, Swanson MS, Cooper TA. Muscleblind proteins regulate alternative splicing. EMBO J. 2004;23(15):3103–12. Scholar
  29. 29.
    Kanadia RN, Johnstone KA, Mankodi A, Lungu C, Thornton CA, Esson D, et al. A muscleblind knockout model for myotonic dystrophy. Science. 2003;302(5652):1978–80. Scholar
  30. 30.
    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 U S A. 2006;103(31):11748–53. Scholar
  31. 31.
    Chamberlain CM, Ranum LP. Mouse model of Muscleblind-like 1 overexpression: skeletal muscle effects and therapeutic promise. Hum Mol Genet. 2012;21(21):4645–54. Scholar
  32. 32.
    Liquori CL, Ricker K, Moseley ML, Jacobsen JF, Kress W, Naylor SL, et al. Myotonic dystrophy type 2 caused by a CCTG expansion in intron 1 of ZNF9. Science. 2001;293(5531):864–7. Scholar
  33. 33.
    Oude Ophuis RJ, Wijers M, Bennink MB, van de Loo FA, Fransen JA, Wieringa B, et al. A tail-anchored myotonic dystrophy protein kinase isoform induces perinuclear clustering of mitochondria, autophagy, and apoptosis. PLoS One. 2009;4(11):e8024. Scholar
  34. 34.
    Harmon EB, Harmon ML, Larsen TD, Yang J, Glasford JW, Perryman MB. Myotonic dystrophy protein kinase is critical for nuclear envelope integrity. J Biol Chem. 2011;286(46):40296–306. Scholar
  35. 35.
    Pellizzoni L, Lotti F, Maras B, Pierandrei-Amaldi P. Cellular nucleic acid binding protein binds a conserved region of the 5′ UTR of Xenopus laevis ribosomal protein mRNAs. J Mol Biol. 1997;267(2):264–75. Scholar
  36. 36.
    Huichalaf C, Schoser B, Schneider-Gold C, Jin B, Sarkar P, Timchenko L. Reduction of the rate of protein translation in patients with myotonic dystrophy 2. J Neurosci. 2009;29(28):9042–9. Scholar
  37. 37.
    Benhalevy D, Gupta SK, Danan CH, Ghosal S, Sun HW, Kazemier HG, et al. The human CCHC-type zinc finger nucleic acid-binding protein binds G-rich elements in target mRNA coding sequences and promotes translation. Cell Rep. 2017;18(12):2979–90. Scholar
  38. 38.
    Mankodi A, Urbinati CR, Yuan QP, Moxley RT, Sansone V, Krym M, et al. Muscleblind localizes to nuclear foci of aberrant RNA in myotonic dystrophy types 1 and 2. Hum Mol Genet. 2001;10(19):2165–70.CrossRefGoogle Scholar
  39. 39.
    Savkur RS, Philips AV, Cooper TA, Dalton JC, Moseley ML, Ranum LP, et al. Insulin receptor splicing alteration in myotonic dystrophy type 2. Am J Hum Genet. 2004;74(6):1309–13. Scholar
  40. 40.
    Kino Y, Washizu C, Kurosawa M, Oma Y, Hattori N, Ishiura S, et al. Nuclear localization of MBNL1: splicing-mediated autoregulation and repression of repeat-derived aberrant proteins. Hum Mol Genet. 2015;24(3):740–56. Scholar
  41. 41.
    Begemann G, Paricio N, Artero R, Kiss I, Perez-Alonso M, Mlodzik M. Muscleblind, a gene required for photoreceptor differentiation in Drosophila, encodes novel nuclear Cys3His-type zinc-finger-containing proteins. Development. 1997;124(21):4321–31.PubMedGoogle Scholar
  42. 42.
    Artero R, Prokop A, Paricio N, Begemann G, Pueyo I, Mlodzik M, et al. The muscleblind gene participates in the organization of Z-bands and epidermal attachments of Drosophila muscles and is regulated by Dmef2. Dev Biol. 1998;195(2):131–43. Scholar
  43. 43.
    Kanadia RN, Urbinati CR, Crusselle VJ, Luo D, Lee YJ, Harrison JK, et al. Developmental expression of mouse muscleblind genes Mbnl1, Mbnl2 and Mbnl3. Gene Expr Patterns. 2003;3(4):459–62.CrossRefGoogle Scholar
  44. 44.
    Kino Y, Mori D, Oma Y, Takeshita Y, Sasagawa N, Ishiura S. Muscleblind protein, MBNL1/EXP, binds specifically to CHHG repeats. Hum Mol Genet. 2004;13(5):495–507. Scholar
  45. 45.
    Du H, Cline MS, Osborne RJ, Tuttle DL, Clark TA, Donohue JP, et al. Aberrant alternative splicing and extracellular matrix gene expression in mouse models of myotonic dystrophy. Nat Struct Mol Biol. 2010;17(2):187–93. Scholar
  46. 46.
    Hao M, Akrami K, Wei K, De Diego C, Che N, Ku JH, et al. Muscleblind-like 2 (Mbnl2) -deficient mice as a model for myotonic dystrophy. Dev Dyn. 2008;237(2):403–10. Scholar
  47. 47.
    Charizanis K, Lee KY, Batra R, Goodwin M, Zhang C, Yuan Y, et al. Muscleblind-like 2-mediated alternative splicing in the developing brain and dysregulation in myotonic dystrophy. Neuron. 2012;75(3):437–50. Scholar
  48. 48.
    Poulos MG, Batra R, Li M, Yuan Y, Zhang C, Darnell RB, et al. Progressive impairment of muscle regeneration in Muscleblind-like 3 isoform knockout mice. Hum Mol Genet. 2013;22(17):3547–58. Scholar
  49. 49.
    Choi J, Dixon DM, Dansithong W, Abdallah WF, Roos KP, Jordan MC, et al. Muscleblind-like 3 deficit results in a spectrum of age-associated pathologies observed in myotonic dystrophy. Sci Rep. 2016;6:30999. Scholar
  50. 50.
    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(12):1887–900. Scholar
  51. 51.
    Choi J, Personius KE, DiFranco M, Dansithong W, Yu C, Srivastava S, et al. Muscleblind-like 1 and Muscleblind-like 3 depletion synergistically enhances myotonia by altering Clc-1 RNA translation. EBioMedicine. 2015;2(9):1034–47. Scholar
  52. 52.
    Warf MB, Berglund JA. MBNL binds similar RNA structures in the CUG repeats of myotonic dystrophy and its pre-mRNA substrate cardiac troponin T. RNA. 2007;13(12):2238–51. Scholar
  53. 53.
    Yuan Y, Compton SA, Sobczak K, Stenberg MG, Thornton CA, Griffith JD, et al. Muscleblind-like 1 interacts with RNA hairpins in splicing target and pathogenic RNAs. Nucleic Acids Res. 2007;35(16):5474–86. Scholar
  54. 54.
    Fu Y, Ramisetty SR, Hussain N, Baranger AM. MBNL1-RNA recognition: contributions of MBNL1 sequence and RNA conformation. Chembiochem. 2012;13(1):112–9. Scholar
  55. 55.
    Hino S, Kondo S, Sekiya H, Saito A, Kanemoto S, Murakami T, et al. Molecular mechanisms responsible for aberrant splicing of SERCA1 in myotonic dystrophy type 1. Hum Mol Genet. 2007;16(23):2834–43. Scholar
  56. 56.
    Teplova M, Patel DJ. Structural insights into RNA recognition by the alternative-splicing regulator Muscleblind-like MBNL1. Nat Struct Mol Biol. 2008;15(12):1343–51. Scholar
  57. 57.
    Goers ES, Purcell J, Voelker RB, Gates DP, Berglund JA. MBNL1 binds GC motifs embedded in pyrimidines to regulate alternative splicing. Nucleic Acids Res. 2010;38(7):2467–84. Scholar
  58. 58.
    Masuda A, Andersen HS, Doktor TK, Okamoto T, Ito M, Andresen BS, et al. CUGBP1 and MBNL1 preferentially bind to 3′ UTRs and facilitate mRNA decay. Sci Rep. 2012;2:209. Scholar
  59. 59.
    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(4):710–24. Scholar
  60. 60.
    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. Scholar
  61. 61.
    Konieczny P, Stepniak-Konieczna E, Sobczak K. MBNL proteins and their target RNAs, interaction and splicing regulation. Nucleic Acids Res. 2014;42(17):10873–87. Scholar
  62. 62.
    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(6):862–72. Scholar
  63. 63.
    Wheeler TM, Lueck JD, Swanson MS, Dirksen RT, Thornton CA. Correction of ClC-1 splicing eliminates chloride channelopathy and myotonia in mouse models of myotonic dystrophy. J Clin Invest. 2007;117(12):3952–7. Scholar
  64. 64.
    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(6):720–5. Scholar
  65. 65.
    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(6):1312–24. Scholar
  66. 66.
    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(15):2189–200. Scholar
  67. 67.
    Zhao Y, Ogawa H, Yonekura S, Mitsuhashi H, Mitsuhashi S, Nishino I, et al. Functional analysis of SERCA1b, a highly expressed SERCA1 variant in myotonic dystrophy type 1 muscle. Biochim Biophys Acta. 2015;1852(10 Pt A):2042–7. Scholar
  68. 68.
    Nakamori M, Kimura T, Fujimura H, Takahashi MP, Sakoda S. Altered mRNA splicing of dystrophin in type 1 myotonic dystrophy. Muscle Nerve. 2007;36(2):251–7. Scholar
  69. 69.
    Rau F, Laine J, Ramanoudjame L, Ferry A, Arandel L, Delalande O, et al. Abnormal splicing switch of DMD's penultimate exon compromises muscle fibre maintenance in myotonic dystrophy. Nat Commun. 2015;6:7205. Scholar
  70. 70.
    Gao Z, Cooper TA. Reexpression of pyruvate kinase M2 in type 1 myofibers correlates with altered glucose metabolism in myotonic dystrophy. Proc Natl Acad Sci U S A. 2013;110(33):13570–5. Scholar
  71. 71.
    Lazarus A, Varin J, Babuty D, Anselme F, Coste J, Duboc D. Long-term follow-up of arrhythmias in patients with myotonic dystrophy treated by pacing: a multicenter diagnostic pacemaker study. J Am Coll Cardiol. 2002;40(9):1645–52.CrossRefGoogle Scholar
  72. 72.
    Groh WJ, Groh MR, Saha C, Kincaid JC, Simmons Z, Ciafaloni E, et al. Electrocardiographic abnormalities and sudden death in myotonic dystrophy type 1. N Engl J Med. 2008;358(25):2688–97. Scholar
  73. 73.
    Harada K, Morimoto S. Inherited cardiomyopathies as a troponin disease. Jpn J Physiol. 2004;54(4):307–18.CrossRefGoogle Scholar
  74. 74.
    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(19):2143–55.CrossRefGoogle Scholar
  75. 75.
    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(24):3079–88. Scholar
  76. 76.
    Oyamada R, Hayashi M, Katoh Y, Tsuchiya K, Mizutani T, Tominaga I, et al. Neurofibrillary tangles and deposition of oxidative products in the brain in cases of myotonic dystrophy. Neuropathology. 2006;26(2):107–14.CrossRefGoogle Scholar
  77. 77.
    Goodwin M, Mohan A, Batra R, Lee KY, Charizanis K, Fernandez Gomez FJ, et al. MBNL sequestration by toxic RNAs and RNA misprocessing in the myotonic dystrophy brain. Cell Rep. 2015;12(7):1159–68. Scholar
  78. 78.
    Orengo JP, Ward AJ, Cooper TA. Alternative splicing dysregulation secondary to skeletal muscle regeneration. Ann Neurol. 2011;69(4):681–90. Scholar
  79. 79.
    Bachinski LL, Baggerly KA, Neubauer VL, Nixon TJ, Raheem O, Sirito M, et al. Most expression and splicing changes in myotonic dystrophy type 1 and type 2 skeletal muscle are shared with other muscular dystrophies. Neuromuscul Disord. 2014;24(3):227–40. Scholar
  80. 80.
    Adereth Y, Dammai V, Kose N, Li R, Hsu T. RNA-dependent integrin alpha3 protein localization regulated by the Muscleblind-like protein MLP1. Nat Cell Biol. 2005;7(12):1240–7. Scholar
  81. 81.
    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(11–12):2266–78. Scholar
  82. 82.
    Wang ET, Ward AJ, Cherone JM, Giudice J, Wang TT, Treacy DJ, et al. Antagonistic regulation of mRNA expression and splicing by CELF and MBNL proteins. Genome Res. 2015;25(6):858–71. Scholar
  83. 83.
    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(7):840–5. Scholar
  84. 84.
    Sicot G, Servais L, Dinca DM, Leroy A, Prigogine C, Medja F, et al. Downregulation of the glial GLT1 glutamate transporter and purkinje cell dysfunction in a mouse model of myotonic dystrophy. Cell Rep. 2017;19(13):2718–29. Scholar
  85. 85.
    Takahashi N, Sasagawa N, Suzuki K, Ishiura S. The CUG-binding protein binds specifically to UG dinucleotide repeats in a yeast three-hybrid system. Biochem Biophys Res Commun. 2000;277(2):518–23. Scholar
  86. 86.
    Cardani R, Bugiardini E, Renna LV, Rossi G, Colombo G, Valaperta R, et al. Overexpression of CUGBP1 in skeletal muscle from adult classic myotonic dystrophy type 1 but not from myotonic dystrophy type 2. PLoS One. 2013;8(12):e83777. Scholar
  87. 87.
    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(1):68–78. Scholar
  88. 88.
    Wang GS, Kuyumcu-Martinez MN, Sarma S, Mathur N, Wehrens XH, Cooper TA. PKC inhibition ameliorates the cardiac phenotype in a mouse model of myotonic dystrophy type 1. J Clin Invest. 2009;119(12):3797–806. Scholar
  89. 89.
    Timchenko NA, Wang GL, Timchenko LT. RNA CUG-binding protein 1 increases translation of 20-kDa isoform of CCAAT/enhancer-binding protein beta by interacting with the alpha and beta subunits of eukaryotic initiation translation factor 2. J Biol Chem. 2005;280(21):20549–57. Scholar
  90. 90.
    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(10):3706–19. Scholar
  91. 91.
    Timchenko NA, Patel R, Iakova P, Cai ZJ, Quan L, Timchenko LT. Overexpression of CUG triplet repeat-binding protein, CUGBP1, in mice inhibits myogenesis. J Biol Chem. 2004;279(13):13129–39. Scholar
  92. 92.
    Ho TH, Bundman D, Armstrong DL, Cooper TA. Transgenic mice expressing CUG-BP1 reproduce splicing mis-regulation observed in myotonic dystrophy. Hum Mol Genet. 2005;14(11):1539–47. Scholar
  93. 93.
    Ladd AN, Nguyen NH, Malhotra K, Cooper TA. CELF6, a member of the CELF family of RNA-binding proteins, regulates muscle-specific splicing enhancer-dependent alternative splicing. J Biol Chem. 2004;279(17):17756–64. Scholar
  94. 94.
    Ladd AN, Charlet N, Cooper TA. The CELF family of RNA binding proteins is implicated in cell-specific and developmentally regulated alternative splicing. Mol Cell Biol. 2001;21(4):1285–96. Scholar
  95. 95.
    Zhang W, Liu H, Han K, Grabowski PJ. Region-specific alternative splicing in the nervous system: implications for regulation by the RNA-binding protein NAPOR. RNA. 2002;8(5):671–85.CrossRefGoogle Scholar
  96. 96.
    Dhaenens CM, Tran H, Frandemiche ML, Carpentier C, Schraen-Maschke S, Sistiaga A, et al. Mis-splicing of Tau exon 10 in myotonic dystrophy type 1 is reproduced by overexpression of CELF2 but not by MBNL1 silencing. Biochim Biophys Acta. 2011;1812(7):732–42. Scholar
  97. 97.
    Paul S, Dansithong W, Kim D, Rossi J, Webster NJ, Comai L, et al. Interaction of muscleblind, CUG-BP1 and hnRNP H proteins in DM1-associated aberrant IR splicing. EMBO J. 2006;25(18):4271–83. Scholar
  98. 98.
    Kim DH, Langlois MA, Lee KB, Riggs AD, Puymirat J, Rossi JJ. HnRNP H inhibits nuclear export of mRNA containing expanded CUG repeats and a distal branch point sequence. Nucleic Acids Res. 2005;33(12):3866–74. Scholar
  99. 99.
    Ravel-Chapuis A, Belanger G, Yadava RS, Mahadevan MS, DesGroseillers L, Cote J, et al. The RNA-binding protein Staufen1 is increased in DM1 skeletal muscle and promotes alternative pre-mRNA splicing. J Cell Biol. 2012;196(6):699–712. Scholar
  100. 100.
    Bondy-Chorney E, Crawford Parks TE, Ravel-Chapuis A, Klinck R, Rocheleau L, Pelchat M, et al. Staufen1 regulates multiple alternative splicing events either positively or negatively in dm1 indicating its role as a disease modifier. PLoS Genet. 2016;12(1):e1005827. Scholar
  101. 101.
    Ravel-Chapuis A, Klein Gunnewiek A, Belanger G, Crawford Parks TE, Cote J, Jasmin BJ. Staufen1 impairs stress granule formation in skeletal muscle cells from myotonic dystrophy type 1 patients. Mol Biol Cell. 2016;27(11):1728–39. Scholar
  102. 102.
    Pettersson OJ, Aagaard L, Andrejeva D, Thomsen R, Jensen TG, Damgaard CK. DDX6 regulates sequestered nuclear CUG-expanded DMPK-mRNA in dystrophia myotonica type 1. Nucleic Acids Res. 2014;42(11):7186–200. Scholar
  103. 103.
    Laurent FX, Sureau A, Klein AF, Trouslard F, Gasnier E, Furling D, et al. New function for the RNA helicase p68/DDX5 as a modifier of MBNL1 activity on expanded CUG repeats. Nucleic Acids Res. 2012;40(7):3159–71. Scholar
  104. 104.
    Jones K, Wei C, Schoser B, Meola G, Timchenko N, Timchenko L. Reduction of toxic RNAs in myotonic dystrophies type 1 and type 2 by the RNA helicase p68/DDX5. Proc Natl Acad Sci U S A. 2015;112(26):8041–5. Scholar
  105. 105.
    Cho DH, Thienes CP, Mahoney SE, Analau E, Filippova GN, Tapscott SJ. Antisense transcription and heterochromatin at the DM1 CTG repeats are constrained by CTCF. Mol Cell. 2005;20(3):483–9. Scholar
  106. 106.
    Michel L, Huguet-Lachon A, Gourdon G. Sense and antisense DMPK RNA foci accumulate in DM1 tissues during development. PLoS One. 2015;10(9):e0137620. Scholar
  107. 107.
    Gudde A, van Heeringen SJ, de Oude AI, van Kessel IDG, Estabrook J, Wang ET, et al. Antisense transcription of the myotonic dystrophy locus yields low-abundant RNAs with and without (CAG)n repeat. RNA Biol. 2017;14(10):1374–88. Scholar
  108. 108.
    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 U S A. 2011;108(1):260–5. Scholar
  109. 109.
    Zu T, Liu Y, Banez-Coronel M, Reid T, Pletnikova O, Lewis J, et al. RAN proteins and RNA foci from antisense transcripts in C9ORF72 ALS and frontotemporal dementia. Proc Natl Acad Sci U S A. 2013;110(51):E4968–77. Scholar
  110. 110.
    Cleary JD, Ranum LP. New developments in RAN translation: insights from multiple diseases. Curr Opin Genet Dev. 2017;44:125–34. Scholar
  111. 111.
    Day JW, Ricker K, Jacobsen JF, Rasmussen LJ, Dick KA, Kress W, et al. Myotonic dystrophy type 2: molecular, diagnostic and clinical spectrum. Neurology. 2003;60(4):657–64.CrossRefGoogle Scholar
  112. 112.
    Meola G, Cardani R. Myotonic dystrophy type 2 and modifier genes: an update on clinical and pathomolecular aspects. Neurol Sci. 2017;38(4):535–46. Scholar
  113. 113.
    Lam LT, Pham YC, Nguyen TM, Morris GE. Characterization of a monoclonal antibody panel shows that the myotonic dystrophy protein kinase, DMPK, is expressed almost exclusively in muscle and heart. Hum Mol Genet. 2000;9(14):2167–73.CrossRefGoogle Scholar
  114. 114.
    Chen W, Wang Y, Abe Y, Cheney L, Udd B, Li YP. Haploinsufficiency for Znf9 in Znf9+/− mice is associated with multiorgan abnormalities resembling myotonic dystrophy. J Mol Biol. 2007;368(1):8–17. Scholar
  115. 115.
    Margolis JM, Schoser BG, Moseley ML, Day JW, Ranum LP. DM2 intronic expansions: evidence for CCUG accumulation without flanking sequence or effects on ZNF9 mRNA processing or protein expression. Hum Mol Genet. 2006;15(11):1808–15. Scholar
  116. 116.
    Raheem O, Olufemi SE, Bachinski LL, 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(6):3025–36. Scholar
  117. 117.
    Holt I, Mittal S, Furling D, Butler-Browne GS, Brook JD, Morris GE. Defective mRNA in myotonic dystrophy accumulates at the periphery of nuclear splicing speckles. Genes Cells. 2007;12(9):1035–48. Scholar
  118. 118.
    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(12):4461–72. Scholar
  119. 119.
    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(2):549–63. Scholar
  120. 120.
    Ho TH, Savkur RS, Poulos MG, Mancini MA, Swanson MS, Cooper TA. Colocalization of muscleblind with RNA foci is separable from mis-regulation of alternative splicing in myotonic dystrophy. J Cell Sci. 2005;118(Pt 13):2923–33. Scholar
  121. 121.
    Querido E, Gallardo F, Beaudoin M, Menard C, Chartrand P. Stochastic and reversible aggregation of mRNA with expanded CUG-triplet repeats. J Cell Sci. 2011;124(Pt 10):1703–14. Scholar
  122. 122.
    Dansithong W, Paul S, Comai L, Reddy S. MBNL1 is the primary determinant of focus formation and aberrant insulin receptor splicing in DM1. J Biol Chem. 2005;280(7):5773–80. Scholar
  123. 123.
    Dansithong W, Wolf CM, Sarkar P, Paul S, Chiang A, Holt I, et al. Cytoplasmic CUG RNA foci are insufficient to elicit key DM1 features. PLoS One. 2008;3(12):e3968. Scholar
  124. 124.
    Smith KP, Byron M, Johnson C, Xing Y, Lawrence JB. Defining early steps in mRNA transport: mutant mRNA in myotonic dystrophy type I is blocked at entry into SC-35 domains. J Cell Biol. 2007;178(6):951–64. Scholar
  125. 125.
    Jain A, Vale RD. RNA phase transitions in repeat expansion disorders. Nature. 2017;546(7657):243–7. Scholar
  126. 126.
    Cass D, Hotchko R, Barber P, Jones K, Gates DP, Berglund JA. The four Zn fingers of MBNL1 provide a flexible platform for recognition of its RNA binding elements. BMC Mol Biol. 2011;12:20. Scholar
  127. 127.
    Courchaine EM, Lu A, Neugebauer KM. Droplet organelles? EMBO J. 2016;35(15):1603–12. Scholar
  128. 128.
    Wheeler TM, Sobczak K, Lueck JD, Osborne RJ, Lin X, Dirksen RT, et al. Reversal of RNA dominance by displacement of protein sequestered on triplet repeat RNA. Science. 2009;325(5938):336–9. Scholar
  129. 129.
    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(7409):111–5. Scholar
  130. 130.
    Wagner SD, Struck AJ, Gupta R, Farnsworth DR, Mahady AE, Eichinger K, et al. Dose-dependent regulation of alternative splicing by MBNL proteins reveals biomarkers for myotonic dystrophy. PLoS Genet. 2016;12(9):e1006316. Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  • Yoshihiro Kino
    • 1
    Email author
  • Jun-ichi Satoh
    • 1
  • Shoichi Ishiura
    • 2
  1. 1.Department of Bioinformatics and Molecular NeuropathologyMeiji Pharmaceuticals UniversityTokyoJapan
  2. 2.Faculty of Life and Medical SciencesDoshisha UniversityKyotoJapan

Personalised recommendations