Molecular Genetic Basis of Myotonic Dystrophy

Abstract

Myotonic dystrophy (DM) comprises at least two genetically distinct forms, both of which are caused by expansions of microsatellite repeats. Expansion of a CTG repeat in the DMPK gene leads to DM1, whereas expansion of a CCTG repeat in the ZNF9 gene causes DM2. In both cases, the repeat units may expand to several thousand repeats. Strikingly similar phenotypes, mutation types and pathological findings suggest a common pathogenic mechanism for both DM1 and DM2. However, the differences between DM1 and DM2 may be a consequence of locus‐specific effects involving haploinsufficiency of different genes and downstream events triggered by CUG or CCUG transcripts. Altogether, the complex DM1 and DM2 phenotypes are probably caused by specific combinations of several possible pathogenic pathways in different tissues of individual patients.

Key Concepts:

  • Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are complex multisystemic disorders with highly similar but not identical symptoms.

  • Both DM1 and DM2 are caused by expansions of microsatellite repeats, however, in two distinct genes (DMPK and ZNF9).

  • Mechanisms leading to the DM1 and DM2 symptoms are very complex with several possible pathogenic pathways.

  • The best described pathogenic pathway involves the misregulation of two alternative splicing regulators, CUG‐BP1 (gain of function) and MBNL1 (loss of function), leading to target‐specific splicing alterations.

  • Both CUG‐BP1 and MBNL1 are multifunctional proteins; thus, their activation/sequestration have effect on further cellular functions such as transcription, translation and mRNA decay.

  • Both DM1 and DM2 causing expansions can also lead to decreased levels of proteins coded by genes around and near to the expansion sites, such as DMPK, ZNF9, SIX5 and DMWD.

  • The exact molecular pathogenic mechanism in certain tissues is probably not uniform, it rather represents a specific combination of several distinct pathogenic pathways.

Keywords: CUG‐BP1; DM1; DM2; DMPK; MBNL1; microsatellite expansions; myotonic dystrophy; RNA gain of function; ZNF9

Figure 1.

Schematic view of the possible pathogenic pathways of DM1 and DM2.

close

References

Bachinski LL, Czernuszewicz T, Ramagli LS et al. (2009) Premutation allele pool in myotonic dystrophy type 2. Neurology 72: 490–497.

Berger DS and Ladd AN (2012) Repression of nuclear CELF activity can rescue CELF‐regulated alternative splicing defects in skeletal muscle models of myotonic dystrophy. PLoS Currents 4: RRN1305.

Berul CI, Maguire CT, Aronovitz MJ et al. (1999) DMPK dosage alterations result in atrioventricular conduction abnormalities in a mouse myotonic dystrophy model. Journal of Clinical Investigation 103: R1–R7.

Brook JD, McCurrach ME, Harley HG et al. (1992) 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 68: 799–808.

Chen W, Wang Y, Abe Y et al. (2007) Haploinsuffciency for Znf9 in Znf9+/− mice is associated with multiorgan abnormalities resembling myotonic dystrophy. Journal of Molecular Biology 368: 8–17.

Cho DH, Thienes CP, Mahoney SE et al. (2005) Antisense transcription and heterochromatin at the DM1 CTG repeats are constrained by CTCF. Molecular Cell 20: 483–489.

Dansithong W, Wolf CM, Sarkar P et al. (2008) Cytoplasmic CUG RNA foci are insufficient to elicit key DM1 features. PLoS One 3: e3968.

Davis BM, McCurrach ME, Taneja KL, Singer RH and Housman DE (1997) Expansion of a CUG trinucleotide repeat in the 3′ untranslated region of myotonic dystrophy protein kinase transcripts results in nuclear retention of transcripts. Proceedings of the National Academy of Sciences of the USA 94: 7388–7393

Day JW and Ranum LP (2005) Genetics and molecular pathogenesis of the myotonic dystrophies. Current Neurology and Neuroscience Reports 5: 55–59.

de Die‐Smulders CE, Howeler CJ, Mirandolle JF et al. (1994) Anticipation resulting in elimination of the myotonic dystrophy gene: a follow up study of one extended family. Journal of Medical Genetics 31: 595–601.

Du H, Cline MS, Osborne RJ et al. (2010) Aberrant alternative splicing and extracellular matrix gene expression in mouse models of myotonic dystrophy. Nature Structural and Molecular Biology 17: 187–193.

Ebralidze A, Wang Y, Petkova V, Ebralidse K and Junghans RP (2004) RNA leaching of transcription factors disrupts transcription in myotonic dystrophy. Science 303: 383–387.

Fardaei M, Rogers MT, Thorpe HM et al. (2002) Three proteins, MBNL, MBLL and MBXL, co‐localize in vivo with nuclear foci of expanded‐repeat transcripts in DM1 and DM2 cells. Human Molecular Genetics 11: 805–814.

Giagnacovo M, Malatesta M, Cardani R, Meola G and Pellicciari C (2012) Nuclear ribonucleoprotein‐containing foci increase in size in non‐dividing cells from patients with myotonic dystrophy type 2. Histochemistry and Cell Biology 138: 699–707.

Gomes‐Pereira M, Cooper TA and Gourdon G (2011) Myotonic dystrophy mouse models: towards rational therapy development. Trends in Molecular Medicine 17: 506–517.

Hao M, Akrami K, Wei K et al. (2008) Muscleblind‐like 2 (Mbnl2) ‐deficient mice as a model for myotonic dystrophy. Developmental Dynamics 237: 403–410.

Ho TH, Bundman D, Armstrong DL and Cooper TA (2005a) Transgenic mice expressing CUG‐BP1 reproduce splicing mis‐regulation observed in myotonic dystrophy. Human Molecular Genetics 14: 1539–1547.

Ho TH, Charlet B, Poulos MG et al. (2004) Muscleblind proteins regulate alternative splicing. EMBO Journal 23: 3103–3112.

Ho TH, Savkur RS, Poulos MG et al. (2005b) Colocalization of muscleblind with RNA foci is separable from mis‐regulation of alternative splicing in myotonic dystrophy. Journal of Cell Science 118: 2923–2933.

Holt I, Jacquemin V, Fardaei M et al. (2009) Muscleblind‐like proteins: similarities and differences in normal and myotonic dystrophy muscle. American Journal of Pathology 174: 216–227.

Huichalaf C, Schoser B, Schneider‐Gold C et al. (2009) Reduction of the rate of protein translation in patients with myotonic dystrophy 2. Journal of Neuroscience 29: 9042–9049.

IDMC (2000) New nomenclature and DNA testing guidelines for myotonic dystrophy type 1 (DM1). The International Myotonic Dystrophy Consortium (IDMC). Neurology 54: 1218–1221.

Jansen G, Bachner D, Coerwinkel M et al. (1995) Structural organization and developmental expression pattern of the mouse WD‐repeat gene DMR‐N9 immediately upstream of the myotonic dystrophy locus. Human Molecular Genetics 4: 843–852.

Jones K, Jin B, Iakova P et al. (2011) RNA Foci, CUGBP1, and ZNF9 are the primary targets of the mutant CUG and CCUG repeats expanded in myotonic dystrophies type 1 and type 2. American Journal of Pathology 179: 2475–2489.

Junghans RP (2009) Dystrophia myotonia: why focus on foci? European Journal of Human Genetics 17: 543–553.

Kanadia RN, Johnstone KA, Mankodi A et al. (2003) A muscleblind knockout model for myotonic dystrophy. Science 302: 1978–1980.

Kanadia RN, Shin J, Yuan Y et al. (2006) Reversal of RNA missplicing and myotonia after muscleblind overexpression in a mouse poly(CUG) model for myotonic dystrophy. Proceedings of the National Academy of Sciences of the USA 103: 11748–11753.

Kim DH, Langlois MA, Lee KB et al. (2005) HnRNP H inhibits nuclear export of mRNA containing expanded CUG repeats and a distal branch point sequence. Nucleic Acids Research 33: 3866–3874.

Krol J, Fiszer A, Mykowska A et al. (2007) Ribonuclease dicer cleaves triplet repeat hairpins into shorter repeats that silence specific targets. Molecular Cell 25: 575–586.

Lee JE and Cooper TA (2009) Pathogenic mechanisms of myotonic dystrophy. Biochemical Society Transactions 37: 1281–1286.

Lin X, Miller JW, Mankodi A et al. (2006) Failure of MBNL1‐dependent post‐natal splicing transitions in myotonic dystrophy. Human Molecular Genetics 15: 2087–2097.

Liquori CL, Ricker K, Moseley ML et al. (2001) Myotonic dystrophy type 2 caused by a CCTG expansion in intron 1 of ZNF9. Science 293: 864–867.

Mahadevan MS, Yadava RS, Yu Q et al. (2006) Reversible model of RNA toxicity and cardiac conduction defects in myotonic dystrophy. Nature Genetics 38: 1066–1070.

Mankodi A, Logigian E, Callahan L et al. (2000) Myotonic dystrophy in transgenic mice expressing an expanded CUG repeat. Science 289: 1769–1773.

Mankodi A, Teng‐Umnuay P, Krym M et al. (2003) Ribonuclear inclusions in skeletal muscle in myotonic dystrophy types 1 and 2. Annals of Neurology 54: 760–768.

Margolis JM, Schoser BG, Moseley ML, Day JW and Ranum LP (2006) DM2 intronic expansions: evidence for CCUG accumulation without flanking sequence or effects on ZNF9 mRNA processing or protein expression. Human Molecular Genetics 15: 1808–1815.

Michalowski S, Miller JW, Urbinati CR et al. (1999) Visualization of double‐stranded RNAs from the myotonic dystrophy protein kinase gene and interactions with CUG‐binding protein. Nucleic Acids Research 27: 3534–3542.

Morales F, Couto JM, Higham CF et al. (2012) Somatic instability of the expanded CTG triplet repeat in myotonic dystrophy type 1 is a heritable quantitative trait and modifier of disease severity. Human Molecular Genetics 21: 3558–3567.

Napierala M and Krzyzosiak WJ (1997) CUG repeats present in myotonin kinase RNA form metastable ‘slippery’ hairpins. Journal of Biological Chemistry 272: 31079–31085.

Osborne RJ, Lin X, Welle S et al. (2009) Transcriptional and post‐transcriptional impact of toxic RNA in myotonic dystrophy. Human Molecular Genetics 18: 1471–1481.

Raheem O, Olufemi SE, Bachinski LL et al. (2010) Mutant (CCTG)n expansion causes abnormal expression of zinc finger protein 9 (ZNF9) in myotonic dystrophy type 2. American Journal of Pathology 177: 3025–3036.

Ravel‐Chapuis A, Belanger G, Yadava RS et al. (2012) The RNA‐binding protein Staufen1 is increased in DM1 skeletal muscle and promotes alternative pre‐mRNA splicing. Journal of Cell Biology 196: 699–712.

Salisbury E, Schoser B, Schneider‐Gold C et al. (2009) Expression of RNA CCUG repeats dysregulates translation and degradation of proteins in myotonic dystrophy 2 patients. American Journal of Pathology 175: 748–762.

Sarkar PS, Appukuttan B, Han J et al. (2000) Heterozygous loss of Six5 in mice is sufficient to cause ocular cataracts. Nature Genetics 25: 110–114.

Schneider C, Ziegler A, Ricker K et al. (2000) Proximal myotonic myopathy: evidence for anticipation in families with linkage to chromosome 3q. Neurology 55: 383–388.

Suominen T, Schoser B, Raheem O et al. (2008) High frequency of co‐segregating CLCN1 mutations among myotonic dystrophy type 2 patients from Finland and Germany. Journal of Neurology 255: 1731–1736.

Taneja KL, McCurrach M, Schalling M, Housman D and Singer RH (1995) Foci of trinucleotide repeat transcripts in nuclei of myotonic dystrophy cells and tissues. Journal of Cell Biology 128: 995–1002.

Timchenko LT, Miller JW, Timchenko NA et al. (1996) Identification of a (CUG)n triplet repeat RNA‐binding protein and its expression in myotonic dystrophy. Nucleic Acids Research 24: 4407–4414.

Timchenko NA, Cai ZJ, Welm AL et al. (2001) RNA CUG repeats sequester CUGBP1 and alter protein levels and activity of CUGBP1. Journal of Biological Chemistry 276: 7820–7826.

Udd B and Krahe R (2012) The myotonic dystrophies: molecular, clinical, and therapeutic challenges. Lancet Neurology 11: 891–905.

Wakimoto H, Maguire CT, Sherwood MC et al. (2002) Characterization of cardiac conduction system abnormalities in mice with targeted disruption of Six5 gene. Journal of Interventional Cardiac Electrophysiology 7: 127–135.

Wang ET, Cody NA, Jog S et al. (2012) Transcriptome‐wide regulation of pre‐mRNA splicing and mRNA localization by muscleblind proteins. Cell 150: 710–724.

Yu Z, Teng X and Bonini NM (2011) Triplet repeat‐derived siRNAs enhance RNA‐mediated toxicity in a Drosophila model for myotonic dystrophy. PLoS Genetics 7: e1001340.

Zu T, Gibbens B, Doty NS et al. (2011) Non‐ATG‐initiated translation directed by microsatellite expansions. Proceedings of the National Academy of Sciences of the USA 108: 260–265.

Further Reading

Batra R, Charizanis K and Swanson MS (2010) Partners in crime: bidirectional transcription in unstable microsatellite disease. Human Molecular Genetics 19: R77–R82.

Klein AF, Gasnier E and Furling D (2011) Gain of RNA function in pathological cases: Focus on myotonic dystrophy. Biochimie 93: 2006–2012.

Mahadevan MS (2012) Myotonic dystrophy: is a narrow focus obscuring the rest of the field? Current Opinion in Neurology 25: 609–613.

Mastroyiannopoulos NP, Shammas C and Phylactou LA (2010) Tackling the pathogenesis of RNA nuclear retention in myotonic dystrophy. Biology of the Cell 102: 515–523.

Ranum LP and Day JW (2004) Myotonic dystrophy: RNA pathogenesis comes into focus. American Journal of Human Geneticss 74: 793–804.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Radvanszky, Jan, and Kadasi, Ludevit(Jan 2013) Molecular Genetic Basis of Myotonic Dystrophy. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0023864]