Clinical and molecular aspects of the myotonic dystrophies: A review

Type 1 myotonic dystrophy or DM1 (Steinert's disease), which is the commonest muscular dystrophy in adults, has intrigued physicians for over a century. Unusual features, compared with other dystrophies, include myotonia, anticipation, and involvement of other organs, notably the brain, eyes, smooth muscle, cardiac conduction apparatus, and endocrine system. Morbidity is high, with a substantial mortality relating to cardiorespiratory dysfunction. More recently a second form of multisystem myotonic disorder has been recognized and variously designated as proximal myotonic myopathy (PROMM), proximal myotonic dystrophy (PDM), or DM2. For both DM1 and DM2 the molecular basis is expansion of an unstable repeat sequence in a noncoding part of a gene (DMPK in DM1 and ZNF9 in DM2). There is accumulating evidence that the basic molecular mechanism is disruption of mRNA metabolism, which has far‐reaching effects on many other genes, in part through the induction of aberrant splicing, explaining the multisystemic nature of the disease. The unstable nature of the expansion provides a molecular explanation for anticipation. This review emphasizes the clinical similarities and differences between DM1 and DM2. It examines current views about the molecular basis of these disorders, and contrasts them with other repeat expansion disorders that have increasingly been recognized as a cause of neurological disease. Muscle Nerve, 2005

[1]  R. Griggs,et al.  Myotonic dystrophy with no trinucleotide repeat expansion , 1994, Annals of neurology.

[2]  T. Cooper,et al.  Loss of the muscle-specific chloride channel in type 1 myotonic dystrophy due to misregulated alternative splicing. , 2002, Molecular cell.

[3]  A. Paetau,et al.  Histopathological differences of myotonic dystrophy type 1 (DM1) and PROMM/DM2 , 2003, Neurology.

[4]  F. Morel,et al.  A novel and unusual case of chronic granulomatous disease in a child with a homozygous 36-bp deletion in the CYBA gene (A220) leading to the activation of a cryptic splice site in intron 4 , 2002, Human Genetics.

[5]  M. Koch,et al.  Multimeric structure of ClC‐1 chloride channel revealed by mutations in dominant myotonia congenita (Thomsen). , 1994, The EMBO journal.

[6]  Y. Kino,et al.  Muscleblind protein, MBNL1/EXP, binds specifically to CHHG repeats. , 2004, Human molecular genetics.

[7]  G. Meola,et al.  Report of the 115th ENMC workshop: DM2/PROMM and other myotonic dystrophies 3rd Workshop, 14–16 February 2003, Naarden, The Netherlands , 2003, Neuromuscular Disorders.

[8]  C. Amemiya,et al.  Characterization of the myotonic dystrophy region predicts multiple protein isoform–encoding mRNAs , 1992, Nature Genetics.

[9]  W. Gish,et al.  Gene structure prediction and alternative splicing analysis using genomically aligned ESTs. , 2001, Genome research.

[10]  S. Chew,et al.  Putting some spine into alternative splicing. , 2003, Trends in biotechnology.

[11]  T. Cooper,et al.  Insulin receptor splicing alteration in myotonic dystrophy type 2. , 2004, American journal of human genetics.

[12]  R. Gibbs,et al.  Decreased expression of myotonin-protein kinase messenger RNA and protein in adult form of myotonic dystrophy. , 1993, Science.

[13]  David E. Housman,et al.  Expansion of an unstable DNA region and phenotypic variation in myotonic dystrophy , 1992, Nature.

[14]  T. Cooper,et al.  The CELF Family of RNA Binding Proteins Is Implicated in Cell-Specific and Developmentally Regulated Alternative Splicing , 2001, Molecular and Cellular Biology.

[15]  S. Mitake,et al.  [Development of Alzheimer neurofibrillary changes in two autopsy cases of myotonic dystrophy]. , 1989, Rinsho shinkeigaku = Clinical neurology.

[16]  J. Seidman,et al.  The Genetic Basis for Cardiomyopathy from Mutation Identification to Mechanistic Paradigms , 2001, Cell.

[17]  M. Swanson,et al.  Visualization of double-stranded RNAs from the myotonic dystrophy protein kinase gene and interactions with CUG-binding protein. , 1999, Nucleic acids research.

[18]  F. Nuttall,et al.  Plasma insulin in patients with myotonic dystrophy and their relatives. , 1974, Medicine.

[19]  T. Cooper,et al.  Disruption of splicing regulated by a CUG-binding protein in myotonic dystrophy. , 1998, Science.

[20]  R. Dutzler,et al.  X-ray structure of a ClC chloride channel at 3.0 Å reveals the molecular basis of anion selectivity , 2002, Nature.

[21]  C. Junien,et al.  Transgenic mice carrying large human genomic sequences with expanded CTG repeat mimic closely the DM CTG repeat intergenerational and somatic instability. , 2000, Human molecular genetics.

[22]  S. Tapscott,et al.  Triplet repeat expansion in myotonic dystrophy alters the adjacent chromatin structure. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[23]  M. Siciliano,et al.  A novel homeodomain-encoding gene is associated with a large CpG island interrupted by the myotonic dystrophy unstable (CTG)n repeat. , 1995, Human molecular genetics.

[24]  C. Amemiya,et al.  Myotonic dystrophy mutation: an unstable CTG repeat in the 3' untranslated region of the gene. , 1992, Science.

[25]  T. Cooper,et al.  New nomenclature and DNA testing guidelines for myotonic dystrophy type 1 (DM1) , 2000, Neurology.

[26]  T. Cooper,et al.  A single cardiac troponin T gene generates embryonic and adult isoforms via developmentally regulated alternate splicing. , 1985, The Journal of biological chemistry.

[27]  D. Housman,et al.  Mice lacking the myotonic dystrophy protein kinase develop a late onset progressive myopathy , 1996, Nature Genetics.

[28]  M. Tarnopolsky,et al.  Modafinil reduces excessive somnolence and enhances mood in patients with myotonic dystrophy , 2002, Neurology.

[29]  T. Ashizawa,et al.  An unstable triplet repeat in a gene related to myotonic muscular dystrophy. , 1992, Science.

[30]  J. Bourke,et al.  107th ENMC International Workshop: the management of cardiac involvement in muscular dystrophy and myotonic dystrophy. 7th–9th June 2002, Naarden, the Netherlands , 2003, Neuromuscular Disorders.

[31]  M. Aminoff,et al.  Autonomic function in myotonic dystrophy. , 1985, Archives of neurology.

[32]  N. Otsuka,et al.  Presenile appearance of abundant Alzheimer's neurofibrillary tangles without senile plaques in the brain in myotonic dystrophy , 2004, Acta Neuropathologica.

[33]  D. Housman,et al.  Expansion of a CUG trinucleotide repeat in the 3' untranslated region of myotonic dystrophy protein kinase transcripts results in nuclear retention of transcripts. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[34]  M. Swanson,et al.  Identification of a (CUG)n triplet repeat RNA-binding protein and its expression in myotonic dystrophy. , 1996, Nucleic acids research.

[35]  Christopher J. Lee,et al.  Genome-wide detection of alternative splicing in expressed sequences of human genes , 2001, Nucleic Acids Res..

[36]  H. Goebel,et al.  Muscle pathology in 57 patients with myotonic dystrophy type 2 , 2004, Muscle & nerve.

[37]  C. Caskey,et al.  Novel proteins with binding specificity for DNA CTG repeats and RNA CUG repeats: implications for myotonic dystrophy. , 1996, Human molecular genetics.

[38]  Christine E. Seidman,et al.  α-tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: A disease of the sarcomere , 1994, Cell.

[39]  N. Niedermaier,et al.  Proximal Myotonic Myopathy with MRI White Matter Abnormalities of the Brain , 1997, Neurology.

[40]  T. Ogihara,et al.  Comparison of the myotonic dystrophy associated CTG repeat in European and Japanese populations. , 1992, Journal of medical genetics.

[41]  E. Hoffman,et al.  Myotonic dystrophy: evidence for a possible dominant-negative RNA mutation. , 1995, Human molecular genetics.

[42]  J. Mandel,et al.  Muscle-specific alternative splicing of myotubularin-related 1 gene is impaired in DM1 muscle cells. , 2002, Human molecular genetics.

[43]  Rappold,et al.  Human Molecular Genetics , 1996, Nature Medicine.

[44]  E. Nanba,et al.  [Myotonic dystrophy]. , 2005, Nihon rinsho. Japanese journal of clinical medicine.

[45]  F. Wright,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. , 2003, American journal of human genetics.

[46]  S. Tapscott.  Deconstructing Myotonic Dystrophy , 2000, Science.

[47]  R. Moxley,et al.  Proximal myotonic myopathy. Clinical features of a multisystem disorder similar to myotonic dystrophy. , 1995, Archives of neurology.

[48]  B. Wieringa,et al.  Expanding complexity in myotonic dystrophy , 1998, BioEssays : news and reviews in molecular, cellular and developmental biology.

[49]  A. Delacourte,et al.  Mice transgenic for the human myotonic dystrophy region with expanded CTG repeats display muscular and brain abnormalities. , 2001, Human molecular genetics.

[50]  B. Olofsson,et al.  Cardiac involvement in congenital myotonic dystrophy. , 1990, British heart journal.

[51]  S. Tapscott,et al.  Trinucleotide repeat expansion at the myotonic dystrophy locus reduces expression of DMAHP , 1997, Nature Genetics.

[52]  R. Wells,et al.  Preferential nucleosome assembly at DNA triplet repeats from the myotonic dystrophy gene. , 1994, Science.

[53]  Novel chloride channel gene mutations in two unrelated Japanese families with Becker's autosomal recessive generalized myotonia , 1999, Neuromuscular Disorders.

[54]  E. Roeder,et al.  Effect of myotonic dystrophy trinucleotide repeat expansion on DMPK transcription and processing. , 1995, Genomics.

[55]  M. Baiget,et al.  Progression of somatic CTG repeat length heterogeneity in the blood cells of myotonic dystrophy patients. , 1998, Human molecular genetics.

[56]  B. Falck,et al.  Proximal myotonic dystrophy—a family with autosomal dominant muscular dystrophy, cataracts, hearing loss and hypogonadism: heterogeneity of proximal myotonic syndromes? , 1997, Neuromuscular Disorders.

[57]  P. Harper,et al.  Three proteins, MBNL, MBLL and MBXL, co-localize in vivo with nuclear foci of expanded-repeat transcripts in DM1 and DM2 cells. , 2002, Human molecular genetics.

[58]  B. Kay,et al.  Molecular basis of human cardiac troponin T isoforms expressed in the developing, adult, and failing heart. , 1995, Circulation research.

[59]  J. Brookfield,et al.  Myotonic dystrophy: the correlation of (CTG) repeat length in leucocytes with age at onset is significant only for patients with small expansions , 1999, Journal of medical genetics.

[60]  K. Kosik,et al.  Structure and novel exons of the human tau gene. , 1992, Biochemistry.

[61]  A. Delacourte,et al.  Dysregulation of human brain microtubule-associated tau mRNA maturation in myotonic dystrophy type 1. , 2001, Human molecular genetics.

[62]  M. Matsunaga,et al.  Topography of Alzheimer's neurofibrillary change distribution in myotonic dystrophy. , 1990, Clinical neuropathology.

[63]  T. Dörk,et al.  A new type of mutation causes a splicing defect in ATM , 2002, Nature Genetics.

[64]  J. Stradling,et al.  Reduction in excess daytime sleepiness by modafinil in patients with myotonic dystrophy , 2003, Neuromuscular Disorders.

[65]  S. Naylor,et al.  Myotonic Dystrophy Type 2 Caused by a CCTG Expansion in Intron 1 of ZNF9 , 2001, Science.

[66]  J. Griffith,et al.  Expanded CTG triplet blocks from the myotonic dystrophy gene create the strongest known natural nucleosome positioning elements. , 1995, Genomics.

[67]  A. Cruz-Martínez.  Myotonic Dystrophy: Present Management, Future Therapy, First edition, Peter S. Harper, Baziel van Engelen, Bruno Eymard, Douglas E. Wilcox (Eds.). Oxford University Press, New York (2004), 251 pages, ISBN: 0-19-852782-9 , 2005 .

[68]  David E. Housman,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 , 1992, Cell.

[69]  T. Ashizawa,et al.  RNA CUG Repeats Sequester CUGBP1 and Alter Protein Levels and Activity of CUGBP1* , 2001, The Journal of Biological Chemistry.

[70]  John I. Clark,et al.  Mice deficient in Six5 develop cataracts: implications for myotonic dystrophy , 2000, Nature Genetics.

[71]  A. Giese,et al.  Cardiac involvement in proximal myotonic myopathy , 1998, Heart.

[72]  D. Housman,et al.  Foci of trinucleotide repeat transcripts in nuclei of myotonic dystrophy cells and tissues , 1995, The Journal of cell biology.

[73]  K. Suzuki,et al.  The CUG-binding protein binds specifically to UG dinucleotide repeats in a yeast three-hybrid system. , 2000, Biochemical and biophysical research communications.

[74]  L. Surh,et al.  Effect of the myotonic dystrophy (DM) mutation on mRNA levels of the DM gene , 1993, Nature Genetics.

[75]  R. P. Junghans,et al.  RNA Leaching of Transcription Factors Disrupts Transcription in Myotonic Dystrophy , 2004, Science.

[76]  M. Kobayashi,et al.  The insulin receptor in myotonic dystrophy. , 1977, The Journal of clinical endocrinology and metabolism.

[77]  J. Flier,et al.  Tissue-specific expression of two alternatively spliced insulin receptor mRNAs in man. , 1989, Molecular endocrinology.

[78]  Patrick R. Hof,et al.  Tau protein isoforms, phosphorylation and role in neurodegenerative disorders 1 1 These authors contributed equally to this work. , 2000, Brain Research Reviews.

[79]  International Human Genome Sequencing Consortium.  Initial sequencing and analysis of the human genome , 2001, Nature.

[80]  M. Swanson,et al.  Muscleblind localizes to nuclear foci of aberrant RNA in myotonic dystrophy types 1 and 2. , 2001, Human molecular genetics.

[81]  R. Moxley.  Proximal myotonic myopathy: Mini-review of a recently delineated clinical disorder , 1996, Neuromuscular Disorders.

[82]  T. Cooper,et al.  Aberrant regulation of insulin receptor alternative splicing is associated with insulin resistance in myotonic dystrophy , 2001, Nature Genetics.

[83]  A. Williams,et al.  Hyperproinsulinaemia in patients with myotonic dystrophy , 1992, Diabetologia.

[84]  V. Funanage,et al.  Effect of triplet repeat expansion on chromatin structure and expression of DMPK and neighboring genes, SIX5 and DMWD, in myotonic dystrophy. , 2001, Molecular genetics and metabolism.

[85]  A. Delacourte,et al.  Specific tau variants in the brains of patients with myotonic dystrophy , 1996, Neurology.

[86]  W. Hauswirth,et al.  A Muscleblind Knockout Model for Myotonic Dystrophy , 2003, Science.

[87]  H. Ellegren.  Microsatellites: simple sequences with complex evolution , 2004, Nature Reviews Genetics.

[88]  A. Ullrich,et al.  Functionally distinct insulin receptors generated by tissue‐specific alternative splicing. , 1990, The EMBO journal.

[89]  良元 佐々木.  A novel CLCN1 mutation : P480T in a Japanese family with Thomsen's myotonia congenita , 2001 .

[90]  J. Brook,et al.  Myotonic dystrophy is associated with a reduced level of RNA from the DMWD allele adjacent to the expanded repeat. , 1999, Human molecular genetics.

[91]  J. Brook,et al.  Transcriptional abnormality in myotonic dystrophy affects DMPK but not neighboring genes. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[92]  M. Schwartz,et al.  Characterization of two new dominant ClC‐1 channel mutations associated with myotonia , 2003, Muscle & nerve.

[93]  A. Berns,et al.  Abnormal myotonic dystrophy protein kinase levels produce only mild myopathy in mice , 1996, Nature Genetics.

[94]  A. Delacourte,et al.  Pathological proteins Tau 64 and 69 are specifically expressed in the somatodendritic domain of the degenerating cortical neurons during Alzheimer's disease , 1990, Acta Neuropathologica.

[95]  R. J. White,et al.  Myotonic dystrophy in transgenic mice expressing an expanded CUG repeat. , 2000, Science.

[96]  S. Solomon,et al.  Mutations in sarcomere protein genes as a cause of dilated cardiomyopathy. , 2001, The New England journal of medicine.

[97]  P. Hof,et al.  Specific Pathological Tau Protein Variants Characterize Pick's Disease , 1996, Journal of neuropathology and experimental neurology.

[98]  L. Ranum,et al.  Genetic mapping of a second myotonic dystrophy locus , 1998, Nature Genetics.

[99]  C. Liquori,et al.  Myotonic dystrophy type 2: human founder haplotype and evolutionary conservation of the repeat tract. , 2003, American journal of human genetics.

[100]  G. Meola,et al.  A family with an unusual myotonic and myopathic phenotype and no CTG expansion (proximal myotonic myopathy syndrome): a challenge for future molecular studies , 1996, Neuromuscular Disorders.

[101]  D. Housman,et al.  DMPK dosage alterations result in atrioventricular conduction abnormalities in a mouse myotonic dystrophy model. , 1999, The Journal of clinical investigation.

[102]  S. Huson,et al.  Incorrect diagnosis of myotonic dystrophy and its potential consequences revealed by subsequent direct genetic analysis. , 1994, Journal of neurology, neurosurgery, and psychiatry.

[103]  T. Ashizawa,et al.  Somatic mosaicism, germline expansions, germline reversions and intergenerational reductions in myotonic dystrophy males: small pool PCR analyses. , 1995, Human molecular genetics.

[104]  S. Cannon,et al.  Expanded CUG repeats trigger aberrant splicing of ClC-1 chloride channel pre-mRNA and hyperexcitability of skeletal muscle in myotonic dystrophy. , 2002, Molecular cell.

[105]  B. Trink,et al.  p63α Mutations Lead to Aberrant Splicing of Keratinocyte Growth Factor Receptor in the Hay-Wells Syndrome* , 2003, Journal of Biological Chemistry.

[106]  M. Baiget,et al.  Comparison of CTG repeat length expansion and clinical progression of myotonic dystrophy over a five year period. , 1995, Journal of medical genetics.

[107]  B. Byrne,et al.  Recruitment of human muscleblind proteins to (CUG)n expansions associated with myotonic dystrophy , 2000, The EMBO journal.

[108]  S. Diriong,et al.  Human cardiac troponin T: cloning and expression of new isoforms in the normal and failing heart. , 1995, Circulation research.

[109]  R. Moxley,et al.  Expansion of the myotonic dystrophy CTG repeat reduces expression of the flanking DMAHP gene , 1997, Nature Genetics.

[110]  A. Delacourte,et al.  Isoelectric point differentiates PHF-tau from biopsy-derived human brain tau proteins. , 1995, Neuroreport.

[111]  H. Brunner,et al.  Influence of sex of the transmitting parent as well as of parental allele size on the CTG expansion in myotonic dystrophy (DM). , 1993, American journal of human genetics.

[112]  P. Jong,et al.  Detection of an unstable fragment of DNA specific to individuals with myotonic dystrophy , 1992, Nature.

[113]  M. Swanson,et al.  Ribonuclear inclusions in skeletal muscle in myotonic dystrophy types 1 and 2 , 2003, Annals of neurology.