본문 바로가기
HOME> 논문 > 논문 검색상세

논문 상세정보

Mechanisms of Myotonic Dystrophies 1 and 2

Lubov, Timchenko    (Department of Medicine, Section of Cardiovascular Sciences, Baylor College of Medicine  );
  • 초록

    Myotonic Dystrophies type 1 and 2 (DM1/2) are neuromuscular disorders which belong to a group of genetic diseases caused by unstable CTG triplet repeat (DM1) and CCTG tetranucleotide repeat (DM2) expansions. In DM1, CTG repeats are located within the 3' untranslated region of myotonin protein kinase (DMPK) gene on chromosome 19q. DM2 is caused by expansion of CCTG repeats located in the first intron of a gene coding for zinc finger factor 9 on chromosome 3q. The CTG and CCTG expansions are located in untranslated regions and are expressed as pre-mRNAs in nuclei (DM1 and DM2) and as mRNA in cytoplasm (DM1). Investigations of molecular alterations in DM1 discovered a new molecular mechanism responsible for this disease. Expansion of un-translated CUG repeats in the mutant DMPK mRNA disrupts biological functions of two CUG-binding proteins, CUGBP and MNBL. These proteins regulate translation and splicing of mRNAs coding for proteins which play a key role in skeletal muscle function. Expansion of CUG repeats alters these two stages of RNA metabolism in DM1 by titrating CUGBP1 and MNBL into mutant DMPK mRNA-protein complexes. Mouse models, in which levels of CUGBP1 and MNBL were modulated to mimic DM1, showed several symptoms of DM1 disease including muscular dystrophy, cataracts and myotonia. Mis-regulated levels of CUGBP1 in newborn mice cause a delay of muscle development mimicking muscle symptoms of congenital form of DM1 disease. Since expansion of CCTG repeats in DM2 is also located in untranslated region, it is predicted that DM2 mechanisms might be similar to those observed in DM1. However, differences in clinical phenotypes of DM1 and DM2 suggest some specific features in molecular pathways in both diseases. Recent publications suggest that number of pathways affected by RNA CUG and CCUG repeats could be larger than initially thought. Detailed studies of these pathways will help in developing therapy for patients affected with DM1 and DM2.

  • 주제어

    Myotonic dystrophy .   CUG repeats .   CCUG repeats .   CUGBP1 .   MNBL.  

  • 참고문헌 (45)

    1. Cooper TA, Ordahl CP. A single cardiac troponin T gene generates embryonic and adult isoforms via developmentally regulated alternative splicing. J Biol Chem 260: 11140-11148, 1985 
    2. Mankodi A, Urbinati CR, Yuan QP, Moxley RT, Sansone V, Krym M, Henderson D, Schalling M, Swanson MS, Thornton CA. Muscleblind localizes to nuclear foci of aberrant RNA in myotonic dystrophy types 1 and 2. Hum Mol Genet 10: 2165-2170, 2001 
    3. Poli V. The role of C/EBP isoforms in the control of inflammatory and native immunity functions. J Biol Chem 273: 29279-29282, 1998 
    4. Timchenko LT, Timchenko NA, Caskey CT, Roberts R. Novel proteins with binding specificity to DNA CTG and RNA CUG repeats: implications for myotonic dystrophy. Hum Mol Genet 5: 115-121, 1996 
    5. Timchenko NA, Patel R, Iakova P, Cai Z-J, Quan L, Timchenko LT. Overexpression of CUG triplet repeat- binding protein, CUGBP1, in mice inhibits myogenesis. J Biol Chem 279: 13129-13139, 2004 
    6. Fu YH, Pizzuti RG, Fenwick JK Jr, Rajnarayan S, Dunne PW, Dubel J, Nasser GA, Ashizawa T, DeJong P, Wieringa B, Korneluk R, Perryman MB, Epstein HF, Caskey CT. An unstable triplet repeat in a gene related to myotonic muscular dystrophy. Science 255: 1256-1258, 1992 
    7. Udd B, Krahe R, Wallgren-Petterson C, Falck B, Kalimo H. Proximal myotonic dystrophy - a family of with autosomal dominant muscular dystrophy, cataracts, hearing loss and hypogonadism:heterogeneity of proximal myotonic syndromes? Neuromuscul Disord 7: 217-228, 1997 
    8. Brook JD, McCurrah ME, Harley HG, Buckler AJ, Church D, Aburatan H, Hunter K, Stanton VP, Thirion J-P, Hudson T, Sohn R, Zemelman B, Snell RG, Rundle SA, Crow S, Davies J, Shelbourne P, Buxton J, Jones C, Juvonen V, Johnson K, Harper PS, Shaw DJ, Housman DE. Molecular basis of myotonic dystrophy: expansion of atrinucleotide (CTG) repeat at the 3' end of a transcript encoding a protein kinase family member. Cell 68: 799-808, 1992 
    9. Liquori CL, Ricker K, Moseley ML, Jacobsen JF, Kress W, Naylor SL, Day JW, Ranum LPW. Myotonic dystrophy type 2 caused by a CCTG expansion in intron of ZNF9. Science 293: 864-867, 2001 
    10. Ebralidze A, Wang Y, Petkova V, Ebralidze K, Junghans RP. RNA leaching of transcription factors disrupts transcription in myotonic dystrophy. Science 303: 383-387, 2004 
    11. Timchenko NA, Cai Z-J, Welm AL, Reddy S, Ashizawa T, Timchenko LT. RNA CUG repeats sequester and alter protein levels and activity of CUGBP1. J Biol Chem 276: 7820-7826, 2001 
    12. Timchenko LT. Myotonic dystrophy: the role of RNA CUG repeats. Am J Hum Genet 64: 360-364, 1999 
    13. Kanadia RN, Johnstone KA, Mankodi A, Lungu C, Thrornton CA, Esson D, Timmers AM, Hauswirth WW, Swanson MS. A muscleblind knockout model for Myotonic dystrophy. Science 302: 1978-1980, 2003 
    14. Ranum LP, Day JW. Myotonic dystrophy: RNA pathogenesis comes into focus. Am J Hum Genet 74: 793-804, 2004 
    15. Cooper TA, Ordahl CP. A single troponin T gene regulated by different programs in cardiac and skeletal muscle development. Science 226: 979-982, 1984 
    16. Timchenko LT, Miller JW, Timchenko NA, DeVore DR, Datar KV, Lin L, Roberts R, Caskey CT, Swanson MS. Identification of a (CUG) ntriplet repeat binding protein and its expression in myotonic dystrophy. Nucl Acids Res 24: 4407-44116, 1996 
    17. Day JW, Ricker K, Jacobsen JF, Rasmussen LJ, Dick KA, Kress W, Schneider C, Koch MC, Beilman GJ, Harrison AR, Dalton JC, Ranum LPW. Myotonic dystrophy type 2. Neurol 60: 657- 664, 2003 
    18. Luedde T, Duderstadt M, Streetz KL, Tacke F, Kubicka S, Manns MP, Trautwein C. C/EBP beta isoforms LIP and LAP modulate progression of the cell cycle in the regenerating mouse liver. Hepatology 40: 356-365, 2004 
    19. Otten AD, Tapscott SJ. Triplet repeat expansion in myotonic dystrophy alters the adjacent chromatin structure. Proc Natl Acad Sci (USA) 92: 5465-5469, 1995 
    20. Calkhoven CF, Bouwman PRJ, Snippe L, Geert AB. Translation start site multiplicity of the CCAAT/enhancer binding protein $\alpha$ mRNA is dictated by a small 5' open reading frame. Nucl Acids Res 22: 5540-5547, 1994 
    21. Mankodi M, Logigian E, Callahan L, McClain C, White R, Henderson D, Krym M, Thornton CA. Myotonic dystrophy in transgenic mice expressing an expanded CUG repeat. Science 289: 1769-1772, 2000 
    22. Seznec H, Agbulut O, Sergeant N, Savouret C, Ghestem A, Tabti N, Willer JC, Ourth L, Duros Brisson E, Fouquet C, Butler-Browne G, Delacourte A, Junien C, Gourdon G. Mice transgenic for the human myotonic dystrophy with expanded CTG repeats display muscular and brain abnormalities. Hum Mol Genet 10: 2717-2726, 2001 
    23. Wu H, Olson EN. Activation of the MEF2 transcription factor in skeletal muscles from myotonic mice. J Clin Invest 109: 1327-1333, 2002 
    24. Finsterer J. Myotonic Dystrophy type 2. Eur J Neurol 9: 441-447, 2002 
    25. Aslanidis C, Jansen G, Amemiya C, Shutler G, Mahadevan M, Tsilfidis C, Clen C, Alleman J, Wormskamp NG, Vooijs M, Buxton J, Johnson K, Sweets HJM, Lennon GG, Carrano AV, Korneluk RG, Wieringa B, deJong PJ. Cloning of essential myotonic dystrophy region and mapping of the putative defect. Nature 355: 548-551, 1992 
    26. Mahadevan M, Tsilfidis C, Sabourin L, Shutler G, Amemiya C, Jansen G, Neville C, Narang M, Barcelo J, O'Hoy K, Leblond S, Earle-MacDonald J, De Jong PJ, Wieringa B, Korneluk RG. Myotonic dystrophy mutation: an unstable CTG repeat in the 3' untranslated region of the gene. Science 255: 1253-1256, 1992 
    27. Timchenko NA, Iakova P, Cai Z-J, Smith JR, Timchenko LT. Molecular basis for impaired muscle differentiation in myotonic dystrophy. Mol Cell Biol 21: 6927-6938, 2001 
    28. Charlet-B N, Savcur 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 10: 45-43, 2002 
    29. Fardaei M, Larkin K, Brook JD, Hamshere MG. In vivo co localization of MNBL protein with DMPK expanded- repeat transcripts. Nucl Acids Res 29: 2766-2771, 2001 
    30. Amack JD, Mahadevan MS. The myotonic dystrophy expanded CUG repeat track is necessary but not sufficient to disrupt C2C12 myoblast differentiation. Hum Mol Genet 10: 1879-1887, 2001 
    31. Iakova P, Wang G-L, Timchenko, L, Michalak M, Pereira-Smith OM, Smith JR, Timchenko NA. Competition of CUGBP1 and calreticulin for the regulation of p21 translation determined cell fate. EMBO J 23: 407-417, 2004 
    32. Welm AL, Mackey SL, Timchenko LT, Darlington GJ, Timchenko NA. Translational Induction of Liver-enriched Transcriptional Inhibitory Protein during Acute Phase Response Leads to Repression of CCAAT/Enhancer Binding Protein $\alpha$ mRNA. J Biol Chem 275: 27406-27413, 2000 
    33. Zhang P, Wong C, Liu D, Finegold M, Harper WJ, Elledge SJ. P21 (CIP1) and p57 (KIP2) control muscle differentiation at the myogenin step. Genes Dev 13: 213-224, 1999 
    34. Baldwin BR, Timchenko NA, Zahnow CA. Epidermal growth factor receptor stimulation activates the RNA binding protein CUGBP1 and increases expression of C/EBPbeta-LIP in mammary epithelial cells. Mol Cell Biol 24: 3682-3691, 2004 
    35. Molkentin JD, Black BL, Martin JF, Olson EN. Cooperative activation of muscle gene expression by MEF2 and myogenic transcription factors. Cell 83: 1125-11330, 1995 
    36. 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 128: 995-1002, 1995 
    37. Miller JW, Urbinati CR, Teng-Umnuay P, Stenberg MG, Byrne BJ, Thornton CA, Swanson MS. Recruitment of human muscleblind proteins to (CUG)n expansions associated with myotonic dystrophy. EMBO J 19: 4439-4448, 2000 
    38. Timchenko NA, Welm AL, Lu X, Timchenko LT. CUG repeat binding protein (CUGBP1) interacts with the 5' region of C/ EBPbeta mRNA and regulates translation of C/EBPbeta isoforms. Nucl Acids Res 27: 4517-4525, 1999 
    39. Savcur RS, Philips AV, Cooper TA. Aberrant regulation of insulin receptor alternative splicing is associated with insulin resistance in myotonic dystrophy. Nat Genet 29: 40-47, 2001 
    40. Descombes P, Schibler U. A liver-enriched transcriptional activator protein, LAP, and a transcriptional inhibitory protein, LIP, are translated from the same mRNA. Cell 67: 569-579, 1991 
    41. Fu YH, Friedman DL, Richards S, Pearlman JA, Gibbs RA, Pizzuti A, Ashizawa T, Perryman MB, Scarlato G, Fenwick RG, Caskey CT. Decreased expression of myotonin-protein kinase messenger RNA and protein in adult form of myotonic dystrophy. Science 260: 235-238, 1993 
    42. Harper PS. Myotonic Dystrophy. WB Saunders, London, UK, 2001 
    43. Savcur RS, Philips AV, Cooper TA, Dalton JC, Moseley ML, Ranum LPW, Day JW. Insulin receptor splicing alteration in myotonic dystrophy type 2. Am J Hum Genet 74: 1309-1313, 2004 
    44. Calkhoven CF, Muller C, Leutz A. Translational control of C/EBP$\alpha$ and C/EBP$\beta$ isoform expression. Genes & Dev 14: 1920-1932, 2000 
    45. Philips AV, Timchenko LT, Cooper TA. Disruption of splicing of regulated by CUG binding protein in myotonic dystrophy. Science 280: 737-741, 1998 

 활용도 분석

  • 상세보기

    amChart 영역
  • 원문보기

    amChart 영역


  • NDSL :
  • 대한약리학회 : 저널
  • 대한생리학회 : 저널
  • 원문이 없습니다.

유료 다운로드의 경우 해당 사이트의 정책에 따라 신규 회원가입, 로그인, 유료 구매 등이 필요할 수 있습니다. 해당 사이트에서 발생하는 귀하의 모든 정보활동은 NDSL의 서비스 정책과 무관합니다.

원문복사신청을 하시면, 일부 해외 인쇄학술지의 경우 외국학술지지원센터(FRIC)에서
무료 원문복사 서비스를 제공합니다.

NDSL에서는 해당 원문을 복사서비스하고 있습니다. 위의 원문복사신청 또는 장바구니 담기를 통하여 원문복사서비스 이용이 가능합니다.

이 논문과 함께 출판된 논문 + 더보기