Advertisement

Genetics of Myotonic Dystrophy

  • Tohru MatsuuraEmail author
Chapter
  • 370 Downloads

Abstract

Myotonic dystrophy (dystrophia myotonica, DM) is the commonest form of muscular dystrophy affecting adults. This multisystem disorder typically affects the skeletal muscle and is characterized by weakness, wasting, and myotonia; other systemic involvement includes ocular, cardiac, endocrine, and central nervous system dysfunction. DM is classified into two main subtypes: type 1 (DM1) and type 2 (DM2) based on mutations in the dystrophia myotonica protein kinase (DMPK) gene and CCHC-type zinc-finger cellular nucleic acid-binding protein (CNBP) formerly known as the zinc finger 9 (ZNF9) gene, respectively. The multisystem phenotype of DM1 and DM2 is due to the presence of expanded repeats and the attendant effects. DM1 occurs due to the persistence of harmful effects of untranslated RNA transcripts of CTG trinucleotide repeat, which are located in the 3′-untranslated region of the DMPK gene on 19q13. DM2 results from the toxic effects of the untranslated RNA transcripts of CCTG tetranucleotide repeat, which are located in the primary intron of the CNBP gene, on chromosome 3q 21.3. A diagnosis of myotonic dystrophy can be made clinically based on presentation with characteristic features and a positive family history. However, molecular genetic testing for an expanded CTG repeat in the DMPK gene is the gold standard for definitive diagnosis of DM1. If DM1 testing is negative, testing for the CCTG repeat in the CNBP gene is then considered appropriate to establish a diagnosis of DM2.

Keywords

Myotonic dystrophy DM1 DM2 DMPK ZNF9 (CNBPExpanded repeats Molecular genetic testing 

Abbreviations

CNBP

Cellular nucleic acid-binding protein

DM

Myotonic dystrophy

DMPK

Dystrophia myotonica protein kinase

MBNL

Muscle blind-like

PROMM

Proximal myotonic myopathy

RNA

Ribonucleic acid

ZNF9

Zinc-finger nuclease 9

References

  1. 1.
    Ranum LPW, Day JW. Myotonic dystrophy: RNA pathogenesis comes into focus. Am J Hum Genet. 2004;74(5):793–804.  https://doi.org/10.1086/383590.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Ho G, Cardamone M, Farrar M. Congenital and childhood myotonic dystrophy: current aspects of disease and future directions. World J Clin Pediatr. 2015;4(4):66–80.  https://doi.org/10.5409/wjcp.v4.i4.66.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Udd B, Krahe R, Sarma S, et al. The myotonic dystrophies: molecular, clinical, and therapeutic challenges. Lancet Neurol. 2012;11(10):891–905.  https://doi.org/10.1016/S1474-4422(12)70204-1.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Yenigun VB, Sirito M, Amcheslavky A, et al. (CCUG)n RNA toxicity in a Drosophila model of myotonic dystrophy type 2 (DM2) activates apoptosis. Dis Model Mech. 2017;10(8):993–1003.  https://doi.org/10.1242/dmm.026179.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Thornton CA. Myotonic dystrophy. Neurol Clin. 2014;32(3):705–19., , viii.  https://doi.org/10.1016/j.ncl.2014.04.011.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Basil TD Chad DA. Myotonic dystrophy: etiology, clinical features, and diagnosis. https://www.uptodate.com/contents/myotonic-dystrophy-etiology-clinical-features-and-diagnosis. Accessed 24 Aug 2017.
  7. 7.
    Zhang F, Bodycombe NE, Haskell KM, et al. A flow cytometry-based screen identifies MBNL1 modulators that rescue splicing defects in myotonic dystrophy type I. Hum Mol Genet. 2017;36(16):e24.  https://doi.org/10.1093/hmg/ddx190.CrossRefGoogle Scholar
  8. 8.
    Dalton JC, Ranum LP, Day JW. Myotonic dystrophy type 2. Seattle: University of Washington; 1993. http://www.ncbi.nlm.nih.gov/pubmed/20301639. Accessed 24 Aug 2017.Google Scholar
  9. 9.
    Fugier C, Klein AF, Hammer C, 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.  https://doi.org/10.1038/nm.2374.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Philips AV, Timchenko LT, Cooper TA. Disruption of splicing regulated by a CUG-binding protein in myotonic dystrophy. Science. 1998;280(5364):737–41. http://www.ncbi.nlm.nih.gov/pubmed/9563950. Accessed 24 Aug 2017.CrossRefGoogle Scholar
  11. 11.
    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.  https://doi.org/10.1038/ng704.CrossRefGoogle Scholar
  12. 12.
    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.  https://doi.org/10.1016/S1097-2765(02)00572-5.CrossRefGoogle Scholar
  13. 13.
    Musova Z, Mazanec R, Krepelova A, et al. Highly unstable sequence interruptions of the CTG repeat in the myotonic dystrophy gene. Am J Med Genet Part A. 2009;149A(7):1365–74.  https://doi.org/10.1002/ajmg.a.32987.CrossRefPubMedGoogle Scholar
  14. 14.
    Meola G, Cardani R. Myotonic dystrophies: an update on clinical aspects, genetic, pathology, and molecular pathomechanisms. Biochim Biophys Acta. 2015;1852(4):594–606.  https://doi.org/10.1016/j.bbadis.2014.05.019.CrossRefGoogle Scholar
  15. 15.
    Mohr J. A study of linkage in man. Copenhagen: Munksgaard; 1954.Google Scholar
  16. 16.
    O’Brien T, Ball S, Sarfarazi M, Harper PS, Robson EB. Genetic linkage between the loci for myotonic dystrophy and peptidase D. Ann Hum Genet. 1983;47(Pt 2):117–21. http://www.ncbi.nlm.nih.gov/pubmed/6881909. Accessed 24 Aug 2017CrossRefGoogle Scholar
  17. 17.
    Davies KE, Jackson J, Williamson R, et al. Linkage analysis of myotonic dystrophy and sequences on chromosome 19 using a cloned complement 3 gene probe. J Med Genet. 1983;20:259–63. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1049116/pdf/jmedgene00108-0021.pdf. Accessed 25 Aug 2017CrossRefGoogle Scholar
  18. 18.
    Shaw DJ, Brook JD, Meredith AL, Harley HG, Sarfarazi M, Harper PS. Gene mapping and chromosome 19. J Med Genet. 1986;23(1):2–10. http://www.ncbi.nlm.nih.gov/pubmed/3081724. Accessed 24 Aug 2017CrossRefGoogle Scholar
  19. 19.
    Bartlett R, Pericak-Vance M, Yamaoka L, et al. A new probe for the diagnosis of myotonic muscular dystrophy. Science. 1987;235(4796):1648–50. http://science.sciencemag.org/content/235/4796/1648. Accessed 24 Aug 2017CrossRefGoogle Scholar
  20. 20.
    Roses AD, Pericak-Vance MA, Ross DA, Yamaoka L, Bartlett RJ. RFLPs at the D19S19 locus of human chromosome 19 linked to myotonic dystrophy (DM). Nucleic Acids Res. 1986;14(13):5569. http://www.ncbi.nlm.nih.gov/pubmed/3016653. Accessed 24 Aug 2017CrossRefGoogle Scholar
  21. 21.
    Friedrich U, Brunner H, Smeets D, Lambermon E, Ropers H-H. Three-point linkage analysis employing C3 and 19cen markers assigns the myotonic dystrophy gene to 19q. Hum Genet. 1987;75(3):291–3.  https://doi.org/10.1007/BF00281077.CrossRefPubMedGoogle Scholar
  22. 22.
    Brook JD, McCurrach ME, Harley HG, 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;68(4):799–808.  https://doi.org/10.1016/0092-8674(92)90154-5.CrossRefPubMedGoogle Scholar
  23. 23.
    Yamagata H, Nakagawa M, Johnson K, Miki T. Further evidence for a major ancient mutation underlying myotonic dystrophy from linkage disequilibrium studies in the Japanese population. J Hum Genet. 1998;43(4):246–9.  https://doi.org/10.1007/s100380050082.CrossRefPubMedGoogle Scholar
  24. 24.
    De Temmerman N, Sermon K, Seneca S, et al. Intergenerational instability of the expanded CTG repeat in the DMPK gene: studies in human gametes and preimplantation embryos. Am J Hum Genet. 2004;75(2):325–9.  https://doi.org/10.1086/422762.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Harper PS. Major problems in neurology: myotonic dystrophy. London, UK: WB Saunders; 2001.Google Scholar
  26. 26.
    Rakocevic-Stojanovic V, Savic D, Pavlovic S, et al. Intergenerational changes of CTG repeat depending on the sex of the transmitting parent in myotonic dystrophy type 1. Eur J Neurol. 2005;12(3):236–7.  https://doi.org/10.1111/j.1468-1331.2004.01075.x.CrossRefPubMedGoogle Scholar
  27. 27.
    Martorell L, Cobo AM, Baiget M, Naudó M, Poza JJ, Parra J. Prenatal diagnosis in myotonic dystrophy type 1. Thirteen years of experience: implications for reproductive counselling in DM1 families. Prenat Diagn. 2007;27(1):68–72.  https://doi.org/10.1002/pd.1627.CrossRefPubMedGoogle Scholar
  28. 28.
    Moxley RT. The myotonic dystrophies. In: Rosenberg RN, DiMauro S, Paulson HL, Ptacek L NE, editors. The Molecular and Genetic Basis of Neurologic and Psychiatric Disease. Boston, MA: Wolters Kluwer; 2008, pp. 532–541.Google Scholar
  29. 29.
    Wong LJ, Ashizawa T, Monckton DG, Caskey CT, Richards CS. Somatic heterogeneity of the CTG repeat in myotonic dystrophy is age and size dependent. Am J Hum Genet. 1995;56:114–22.PubMedPubMedCentralGoogle Scholar
  30. 30.
    Monckton DG, Wong LI, Ashizawa T, Caskey CT. Somatic mosaicism, germline expansions, germline reversions and intergenerational reductions in myotonic dystrophy males: small pool PCR analyses. Hum Mol Genet. 1995;4:1–8.CrossRefGoogle Scholar
  31. 31.
    Puymirat J, Giguere Y, Mathieu J, Bouchard J-P. Intergenerational contraction of the CTG repeats in 2 families with myotonic dystrophy type 1. Neurology. 2009;73(24):2126–7.  https://doi.org/10.1212/WNL.0b013e3181c677e1.CrossRefPubMedGoogle Scholar
  32. 32.
    Ashizawa T, Anvret M, Baiget M, et al. Characteristics of intergenerational contractions of the CTG repeat in myotonic dystrophy. Am J Hum Genet. 1994;54(3):414–23. http://www.ncbi.nlm.nih.gov/pubmed/8116611. Accessed 24 Aug 2017PubMedPubMedCentralGoogle Scholar
  33. 33.
    Harley HG, Brook JD, Rundle SA, et al. Expansion of an unstable DNA region and phenotypic variation in myotonic dystrophy. Nature. 1992;355(6360):545–6.  https://doi.org/10.1038/355545a0.CrossRefPubMedGoogle Scholar
  34. 34.
    Aslanidis C, Jansen G, Amemiya C, et al. Cloning of the essential myotonic dystrophy region and mapping of the putative defect. Nature. 1992;355(6360):548–51.  https://doi.org/10.1038/355548a0.CrossRefPubMedGoogle Scholar
  35. 35.
    Tsilfidis C, MacKenzie AE, Mettler G, Barceló J, Korneluk RG. Correlation between CTG trinucleotide repeat length and frequency of severe congenital myotonic dystrophy. Nat Genet. 1992;1(3):192–5.  https://doi.org/10.1038/ng0692-192.CrossRefPubMedGoogle Scholar
  36. 36.
    Richards CS, Palomaki GE, Hegde M. Results from an external proficiency testing program: 11 years of molecular genetics testing for myotonic dystrophy type 1. Genet Med. 2016;18(12):1290–4.  https://doi.org/10.1038/gim.2016.59.CrossRefPubMedGoogle Scholar
  37. 37.
    Theadom A, Rodrigues M, Roxburgh R, et al. Prevalence of muscular dystrophies: a systematic literature review. Neuroepidemiology. 2014;43(3–4):259–68.  https://doi.org/10.1159/000369343.CrossRefPubMedGoogle Scholar
  38. 38.
    Yotova V, Labuda D, Zietkiewicz E, et al. Anatomy of a founder effect: myotonic dystrophy in Northeastern Quebec. Hum Genet. 2005;117(2-3):177–87.  https://doi.org/10.1007/s00439-005-1298-8.CrossRefPubMedGoogle Scholar
  39. 39.
    Pratte A, Prévost C, Puymirat J, Mathieu J. Anticipation in myotonic dystrophy type 1 parents with small CTG expansions. Am J Med Genet Part A. 2015;167(4):708–14.  https://doi.org/10.1002/ajmg.a.36950.CrossRefGoogle Scholar
  40. 40.
    Ricker K, Grimm T, Koch MC, et al. Linkage of proximal myotonic myopathy to chromosome 3q. Neurology. 1999;52(1):170–1. http://www.ncbi.nlm.nih.gov/pubmed/9921867. Accessed 24 Aug 2017CrossRefGoogle Scholar
  41. 41.
    Sun C, Henriksen OA, Tranebjaerg L. Proximal myotonic myopathy: clinical and molecular investigation of a Norwegian family with PROMM. Clin Genet. 1999;56(6):457–61.  https://doi.org/10.1034/j.1399-0004.1999.560609.x.CrossRefPubMedGoogle Scholar
  42. 42.
    Udd B, Krahe R, Wallgren-Petterson C, Falck B, Kalimo H. Proximal myotonic dystrophy: a family with autosomal dominant muscular dystrophy, cataracts, hearing loss and hypogonadism: heterogeneity of proximal myotonic syndromes? Neuromuscul Disord. 1997;7:217–28.CrossRefGoogle Scholar
  43. 43.
    Thornton CA, Griggs RC, Moxley RT. Myotonic dystrophy with no trinucleotide repeat expansion. Ann Neurol. 1994;35(3):269–72.  https://doi.org/10.1002/ana.410350305.CrossRefPubMedGoogle Scholar
  44. 44.
    Ranum LPW, Rasmussen PF, Benzow KA, Koob MD, Day JW. Genetic mapping of a second myotonic dystrophy locus. Nat Genet. 1998;19(2):196–8.  https://doi.org/10.1038/570.CrossRefPubMedGoogle Scholar
  45. 45.
    Day JW, Roelofs R, Leroy B, Pech I, Benzow K, Ranum LP. Clinical and genetic characteristics of a five-generation family with a novel form of myotonic dystrophy (DM2). Neuromuscul Disord. 1999;9(1):19–27. http://www.ncbi.nlm.nih.gov/pubmed/10063831. Accessed 4 Sep 2017CrossRefGoogle Scholar
  46. 46.
    Liquori CL, Ricker K, Moseley ML, et al. Myotonic dystrophy type 2 caused by a CCTG expansion in intron 1 of ZNF9. Science. 2001;293(5531):864–7.  https://doi.org/10.1126/science.1062125.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    * 118425 CHLORIDE CHANNEL 1, SKELETAL MUSCLE; CLCN1. http://omim.org/entry/118425#0010.Google Scholar
  48. 48.
    Mastaglia FL, Harker N, Phillips BA, et al. Dominantly inherited proximal myotonic myopathy and leukoencephalopathy in a family with an incidental CLCN1 mutation. J Neurol Neurosurg Psychiatry. 1998;64(4):543–7. http://www.ncbi.nlm.nih.gov/pubmed/9576553. Accessed 24 Aug 2017CrossRefGoogle Scholar
  49. 49.
    Day JW, Ricker K, Jacobsen JF, et al. Myotonic dystrophy type 2: molecular, diagnostic and clinical spectrum. Neurology. 2003;60(4):657–64. http://www.ncbi.nlm.nih.gov/pubmed/12601109. Accessed 25 Aug 2017CrossRefGoogle Scholar
  50. 50.
    Bachinski LL, Czernuszewicz T, Ramagli LS, et al. Premutation allele pool in myotonic dystrophy type 2. Neurology. 2009;72(6):490–7.  https://doi.org/10.1212/01.wnl.0000333665.01888.33.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Kurosaki T, Ueda S, Ishida T, Abe K, Ohno K, Matsuura T. The Unstable CCTG Repeat Responsible for Myotonic Dystrophy Type 2 Originates from an AluSx Element Insertion into an Early Primate Genome. PLoS One. 2012;7(6):e38379.  https://doi.org/10.1371/journal.pone.0038379.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Dere R, Wells RD. DM2 CCTG•CAGG repeats are crossover hotspots that are more prone to expansions than the DM1 CTG•CAG repeats in Escherichia coli. J Mol Biol. 2006;360(1):21–36.  https://doi.org/10.1016/j.jmb.2006.05.012.CrossRefPubMedGoogle Scholar
  53. 53.
    Lam SL, Wu F, Yang H, Chi LM. The origin of genetic instability in CCTG repeats. Nucleic Acids Res. 2011;39(14):6260–8.  https://doi.org/10.1093/nar/gkr185.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Schoser BG, Kress W, Walter MC, Halliger-Keller B, Lochmüller H, Ricker K. Homozygosity for CCTG mutation in myotonic dystrophy type 2. Brain. 2004;127(Pt 8):1868–77. Epub 2004 Jul 1CrossRefGoogle Scholar
  55. 55.
    Schneider C, Ziegler A, Ricker K, et al. Proximal myotonic myopathy: evidence for anticipation in families with linkage to chromosome 3q. Neurology. 2000;55(3):383–8. http://www.ncbi.nlm.nih.gov/pubmed/10932272. Accessed 4 Sep 2017CrossRefGoogle Scholar
  56. 56.
    Dalton JC, Ranum LPW, Day JW. Myotonic dystrophy type 2. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle WA: University of Washington, Seattle; 2006. https://www.ncbi.nlm.nih.gov/books/NBK1466/.Google Scholar
  57. 57.
    Udd B, Meola G, Krahe R, et al. Report of the 115th ENMC workshop: DM2/PROMM and other myotonic dystrophies. 3rd Workshop, 14-16 February 2003, Naarden, The Netherlands. Neuromuscul Disord. 2003;13(7-8):589–96.  https://doi.org/10.1016/S0960-8966(03)00092-0.CrossRefPubMedGoogle Scholar
  58. 58.
    Suominen T, Bachinski LL, Auvinen S, et al. Population frequency of myotonic dystrophy: higher than expected frequency of myotonic dystrophy type 2 (DM2) mutation in Finland. Eur J Hum Genet. 2011;19(7):776–82.  https://doi.org/10.1038/ejhg.2011.23.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Liquori CL, Ikeda Y, Weatherspoon M, et al. Myotonic dystrophy type 2: human founder haplotype and evolutionary conservation of the repeat tract. Am J Hum Genet. 2003;73(4):849–62.  https://doi.org/10.1086/378720.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Bachinski LL, Udd B, Meola G, et al. Confirmation of the type 2 myotonic dystrophy (CCTG)n expansion mutation in patients with proximal myotonic myopathy/proximal myotonic dystrophy of different European origins: a single shared haplotype indicates an ancestral founder effect. Am J Hum Genet. 2003;73(4):835–48.  https://doi.org/10.1086/378566.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Coenen MJH, Tieleman AA, Schijvenaars MMVAP, et al. Dutch myotonic dystrophy type 2 patients and a North-African DM2 family carry the common European founder haplotype. Eur J Hum Genet. 2011;19(5):567–70.  https://doi.org/10.1038/ejhg.2010.233.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Saito T, Amakusa Y, Kimura T, et al. Myotonic dystrophy type 2 in Japan: ancestral origin distinct from Caucasian families. Neurogenetics. 2008;9(1):61–3.  https://doi.org/10.1007/s10048-007-0110-4.CrossRefPubMedGoogle Scholar
  63. 63.
    Nakayama T, Nakamura H, Oya Y, et al. Clinical and genetic analysis of the first known Asian family with myotonic dystrophy type 2. J Hum Genet. 2014;59(3):129–33.  https://doi.org/10.1038/jhg.2013.133.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    New nomenclature and DNA testing guidelines for myotonic dystrophy type 1 (DM1). The International Myotonic Dystrophy Consortium (IDMC). Neurology. 2000;54(6):1218–1221. http://www.ncbi.nlm.nih.gov/pubmed/10746587. Accessed 25 Aug 2017.Google Scholar
  65. 65.
    Savić Pavićević D, Miladinović J, Brkušanin M, et al. Molecular genetics and genetic testing in myotonic dystrophy type 1. Biomed Res Int. 2013;2013:1–13.  https://doi.org/10.1155/2013/391821.CrossRefGoogle Scholar
  66. 66.
    Radvansky J, Ficek A, Kadasi L. Upgrading molecular diagnostics of myotonic dystrophies: Multiplexing for simultaneous characterization of the DMPK and ZNF9 repeat motifs. Mol Cell Probes. 2011;25(4):182–5.  https://doi.org/10.1016/j.mcp.2011.04.006.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  1. 1.Division of Neurology, Department of MedicineJichi Medical UniversityShimotsukeJapan

Personalised recommendations