Top

Published in:

01-04-2010 | Original Paper

Differences in aberrant expression and splicing of sarcomeric proteins in the myotonic dystrophies DM1 and DM2

Authors: Anna Vihola, Linda L. Bachinski, Mario Sirito, Shodimu-Emmanuel Olufemi, Shohrae Hajibashi, Keith A. Baggerly, Olayinka Raheem, Hannu Haapasalo, Tiina Suominen, Jeanette Holmlund-Hampf, Anders Paetau, Rosanna Cardani, Giovanni Meola, Hannu Kalimo, Lars Edström, Ralf Krahe, Bjarne Udd

Published in: Acta Neuropathologica | Issue 4/2010

Abstract

Aberrant transcription and mRNA processing of multiple genes due to RNA-mediated toxic gain-of-function has been suggested to cause the complex phenotype in myotonic dystrophies type 1 and 2 (DM1 and DM2). However, the molecular basis of muscle weakness and wasting and the different pattern of muscle involvement in DM1 and DM2 are not well understood. We have analyzed the mRNA expression of genes encoding muscle-specific proteins and transcription factors by microarray profiling and studied selected genes for abnormal splicing. A subset of the abnormally regulated genes was further analyzed at the protein level. TNNT3 and LDB3 showed abnormal splicing with significant differences in proportions between DM2 and DM1. The differential abnormal splicing patterns for TNNT3 and LDB3 appeared more pronounced in DM2 relative to DM1 and are among the first molecular differences reported between the two diseases. In addition to these specific differences, the majority of the analyzed genes showed an overall increased expression at the mRNA level. In particular, there was a more global abnormality of all different myosin isoforms in both DM1 and DM2 with increased transcript levels and a differential pattern of protein expression. Atrophic fibers in DM2 patients expressed only the fast myosin isoform, while in DM1 patients they co-expressed fast and slow isoforms. However, there was no increase of total myosin protein levels, suggesting that aberrant protein translation and/or turnover may also be involved.

Available only for authorised users

Allen DL, Leinwand LA (2002) Intracellular calcium and myosin isoform transitions. Calcineurin and calcium-calmodulin kinase pathways regulate preferential activation of the IIa myosin heavy chain promoter. J Biol Chem 277(47):45323–45330CrossRefPubMed

Allen DL, Weber JN, Sycuro LK, Leinwand LA (2005) Myocyte enhancer factor-2 and serum response factor binding elements regulate fast myosin heavy chain transcription in vivo. J Biol Chem 280(17):17126–17134CrossRefPubMed

Auvinen S, Suominen T, Hannonen P, Bachinski LL, Krahe R, Udd B (2008) Myotonic dystrophy type 2 found in two of sixty-three persons diagnosed as having fibromyalgia. Arthritis Rheum 58(11):3627–3631CrossRefPubMed

Bachinski LL, Udd B, Meola G et al (2003) 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 73(4):835–8485CrossRefPubMed

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(4):799–808CrossRefPubMed

Brotto MA, Biesiadecki BJ, Brotto LS, Nosek TM, Jin JP (2006) Coupled expression of troponin T and troponin I isoforms in single skeletal muscle fibers correlates with contractility. Am J Physiol Cell Physiol 290(2):567–576CrossRef

Buj-Bello A, Furling D, Tronchere H et al (2002) Muscle-specific alternative splicing of myotubularin-related 1 gene is impaired in DM1 muscle cells. Hum Mol Genet 11(19):2297–2307CrossRefPubMed

Charlet-Berguerand N, Savkur RS, Singh G, Philips AV, Grice EA, Cooper TA (2002) Loss of the muscle-specific chloride channel in type 1 myotonic dystrophy due to misregulated alternative splicing. Mol Cell 10(1):45–53CrossRef

Day JW, Ricker K, Jacobsen JF et al (2003) Myotonic dystrophy type 2: molecular, diagnostic and clinical spectrum. Neurology 60(4):657–664PubMed

10.

Dubowitz V, Sewry CA (2007) Immunohistochemistry. In: muscle biopsy—a practical approach, 3rd edn. Saunders Elsevier, UK, pp 195–245

11.

Ebralidze A, Wang Y, Petkova V, Ebralidse K, Junghans RP (2004) RNA leaching of transcription factors disrupts transcription in myotonic dystrophy. Science 303(5656):383–387CrossRefPubMed

12.

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. Hum Mol Genet 11(7):805–814CrossRefPubMed

13.

Faulkner G, Pallavicini A, Formentin E et al (1999) ZASP: a new Z-band alternatively spliced PDZ-motif protein. J Cell Biol 146(2):465–475CrossRefPubMed

14.

Fu YH, Pizzuti A, Fenwick RG Jr et al (1992) An unstable triplet repeat in a gene related to myotonic muscular dystrophy. Science 255(5049):1256–1258CrossRefPubMed

15.

Grifone R, Laclef C, Spitz F et al (2004) Six1 and Eya1 expression can reprogram adult muscle from the slow-twitch phenotype into the fast-twitch phenotype. Mol Cell Biol 24(14):6253–6267CrossRefPubMed

16.

Griggs R, Vihola A, Hackman P et al (2007) Zaspopathy in a large classic late-onset distal myopathy family. Brain 130(Pt 6):1477–1484CrossRefPubMed

17.

Haravuori H, Vihola A, Straub V et al (2001) Secondary calpain3 deficiency in 2q-linked muscular dystrophy: titin is the candidate gene. Neurology 56(7):869–877PubMed

18.

Harper PS (2001) Myotonic dystrophy. Saunders, London

19.

Horton MJ, Brandon CA, Morris TJ, Braun TW, Yaw KM, Sciote JJ (2001) Abundant expression of myosin heavy-chain IIB RNA in a subset of human masseter muscle fibres. Arch Oral Biol 46(11):1039–1050CrossRefPubMed

20.

Huang C, Zhou Q, Liang P et al (2003) Characterization and in vivo functional analysis of splice variants of cypher. J Biol Chem 278(9):7360–7365CrossRefPubMed

21.

Huichalaf C, Schoser B, Schneider-Gold C, Jin B, Sarkar P, Timchenko L (2009) Reduction of the rate of protein translation in patients with myotonic dystrophy 2. J Neurosci 29(28):9042–9049CrossRefPubMed

22.

Jin J, Wang G-L, Salisbury E, Timchenko L, Timchenko NA (2009) GSK3β-cyclin D3-CUGBP1-eIF2 pathway in aging and in myotonic dystrophy. Cell Cycle 8(15):2356–2360PubMed

23.

Kanadia RN, Johnstone KA, Mankodi A et al (2003) A muscleblind knockout model for myotonic dystrophy. Science 302(5652):1978–1980CrossRefPubMed

24.

Kimura T, Nakamori M, Lueck JD et al (2005) Altered mRNA splicing of the skeletal muscle ryanodine receptor and sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase in myotonic dystrophy type 1. Hum Mol Genet 14(15):2189–2200CrossRefPubMed

25.

Konig S, Beguet A, Bader CR, Bernheim L (2006) The calcineurin pathway links hyperpolarization (Kir2.1)-induced Ca²⁺ signals to human myoblast differentiation and fusion. Development 133(16):3107–3114CrossRefPubMed

26.

Krahe R, Bachinski LL, Udd B (2006) Myotonic dystrophy type 2: clinical and genetic aspects. In: Wells RD, Ashizawa T (eds) Genetic instabilities and neurological diseases, 2nd edn. Academic Press, Boston, pp 131–150

27.

Leroy O, Wang J, Maurage CA et al (2006) Brain-specific change in alternative splicing of tau exon 6 in myotonic dystrophy type 1. Biochim Biophys Acta 1762(4):460–467PubMed

28.

Lin X, Miller JW, Mankodi A et al (2006) Failure of MBNL1-dependent post-natal splicing transitions in myotonic dystrophy. Hum Mol Genet 15(13):2087–2097CrossRefPubMed

29.

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(5531):864–867CrossRefPubMed

30.

Machuca-Tzili L, Thorpe H, Robinson TE, Sewry C, Brook JD (2006) Flies deficient in muscleblind protein model features of myotonic dystrophy with altered splice forms of Z-band associated transcripts. Hum Genet 120(4):487–499CrossRefPubMed

31.

Mahadevan M, Tsilfidis C, Sabourin L et al (1992) Myotonic dystrophy mutation: an unstable CTG repeat in the 3′ untranslated region of the gene. Science 255(5049):1253–1255CrossRefPubMed

32.

Mahadevan MS, Yadava RS, Yu Q et al (2006) Reversible model of RNA toxicity and cardiac conduction defects in myotonic dystrophy. Nat Genet 38(9):1066–1070CrossRefPubMed

33.

Mankodi A, Logigian E, Callahan L et al (2000) Myotonic dystrophy in transgenic mice expressing an expanded CUG repeat. Science 289(5485):1769–1773CrossRefPubMed

34.

Mankodi A, Takahashi MP, Jiang H et al (2002) Expanded CUG repeats trigger aberrant splicing of ClC-1 chloride channel pre-mRNA and hyperexcitability of skeletal muscle in myotonic dystrophy. Mol Cell 100(1):35–44CrossRef

35.

Mankodi A, Lin X, Blaxall BC, Swanson MS, Thornton CA (2005) Nuclear RNA foci in the heart in myotonic dystrophy. Circ Res 97(11):1152–1155CrossRefPubMed

36.

Maurage CA, Udd B, Ruchoux MM et al (2005) Similar brain tau pathology in DM2/PROMM and DM1/Steinert disease. Neurology 65(10):1636–1638CrossRefPubMed

37.

McKinsey TA, Zhang CL, Olson EN (2002) MEF2: a calcium-dependent regulator of cell division, differentiation and death. Trends Biochem Sci 27(1):40–47CrossRefPubMed

38.

Molkentin JD, Firulli AB, Black BL et al (1996) MEF2B is a potent transactivator expressed in early myogenic lineages. Mol Cell Biol 16(7):3814–3824PubMed

39.

Moraes KCM, Wilusz CJ, Wilusz J (2006) CUG-BP binds to RNA substrates and recruits PARN deadenylase. RNA 12:1084–1091CrossRefPubMed

40.

Olive M, Martinez-Matos JA, Pirretas P, Povedano M, Navarro C, Ferrer I (1997) Expression of myogenic regulatory factors (MRFs) in human neuromuscular disorders. Neuropathol Appl Neurobiol 23(6):475–482CrossRefPubMed

41.

Osborne RJ, Thornton CA (2006) RNA-dominant diseases. Hum Mol Genet 15(Spec No 2):R162–R169CrossRefPubMed

42.

Philips AV, Timchenko LT, Cooper TA (1998) Disruption of splicing regulated by a CUG-binding protein in myotonic dystrophy. Science 280(5364):737–741CrossRefPubMed

43.

Potthoff MJ, Wu H, Arnold MA et al (2007) Histone deacetylase degradation and MEF2 activation promote the formation of slow-twitch myofibers. J Clin Investig 117:2459–2467CrossRefPubMed

44.

Ranum LP, Cooper TA (2006) RNA-mediated neuromuscular disorders. Annu Rev Neurosci 29:259–277CrossRefPubMed

45.

Ricker K, Koch MC, Lehmann-Horn F et al (1995) Proximal myotonic myopathy. Clinical features of a multisystemic disorder similar to myotonic dystrophy. Arch Neurol 52(1):25–31PubMed

46.

Sallinen R, Vihola A, Bachinski LL et al (2004) New methods for molecular diagnosis and demonstration of the (CCTG)n mutation in myotonic dystrophy type 2 (DM2). Neuromuscul Disord 14(4):274–283CrossRefPubMed

47.

Salisbury E, Sakai K, Schoser B et al (2008) Ectopic expression of cyclin D3 corrects differentiation of DM1 myoblasts through activation of RNA CUG-binding protein, CUGBP1. Exp Cell Res 314:2266–2278CrossRefPubMed

48.

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. Am J Pathol 175(2):748–762CrossRefPubMed

49.

Salvatori S, Furlan S, Fanin M et al (2009) Comparative transcriptional and biochemical studies in muscle of myotonic dystrophies (DM1 and DM2). Neurol Sci 30(3):185–192CrossRefPubMed

50.

Savkur RS, Philips AV, Cooper TA (2001) Aberrant regulation of insulin receptor alternative splicing is associated with insulin resistance in myotonic dystrophy. Nat Genet 29(1):40–47CrossRefPubMed

51.

Savkur RS, Philips AV, Cooper TA et al (2004) Insulin receptor splicing alteration in myotonic dystrophy type 2. Am J Hum Genet 74(6):1309–1313CrossRefPubMed

52.

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

53.

Schoser BG, Schneider-Gold C, Kress W et al (2004) Muscle pathology in 57 patients with myotonic dystrophy type 2. Muscle Nerve 29(2):275–281CrossRefPubMed

54.

Selcen D, Engel AG (2005) Mutations in ZASP define a novel form of muscular dystrophy in humans. Ann Neurol 57(2):269–276CrossRefPubMed

55.

Stewart AF, Richard CW 3rd, Suzow J et al (1996) Cloning of human RTEF-1, a transcriptional enhancer factor-1-related gene preferentially expressed in skeletal muscle: evidence for an ancient multigene family. Genomics 37(1):68–76CrossRefPubMed

56.

Taneja KL, McCurrach M, Schalling M, Housman D, Singer RH (1995) Foci of trinucleotide repeat transcripts in nuclei of myotonic dystrophy cells and tissues. J Cell Biol 128(6):995–1002CrossRefPubMed

57.

Timchenko NA, Cai ZJ, Welm AL, Reddy S, Ashizawa T, Timchenko LT (2001) RNA CUG repeats sequester CUGBP1 and alter protein levels and activity of CUGBP1. J Biol Chem 276(11):7820–7826CrossRefPubMed

58.

Timchenko NA, Iakova P, Cai Z-J, Smith JR, Timchenko LT (2001) Molecular basis for impaired muscle differentiation in myotonic dystrophy. Mol Cell Biol 21:6927–6938CrossRefPubMed

59.

Timchenko NA, Patel R, Iakova P, Cai ZJ, Quan L, Timchenko LT (2004) Overexpression of CUG triplet repeat-binding protein, CUGBP1, in mice inhibits myogenesis. J Biol Chem 279(13):13129–13139CrossRefPubMed

60.

Tschirgi ML, Rajapakse I, Chandra M (2006) Functional consequence of mutation in rat cardiac troponin T is affected differently by myosin heavy chain isoforms. J Physiol 574(Pt 1):263–273CrossRefPubMed

61.

Udd B, Krahe R, Wallgren-Pettersson C, Falck B, Kalimo H (1997) Proximal myotonic dystrophy—a family with autosomal dominant muscular dystrophy, cataracts, hearing loss and hypogonadism: heterogeneity of proximal myotonic syndromes? Neuromuscul Disord 7(4):217–228CrossRefPubMed

62.

Udd B, Meola G, Krahe R et al (2003) Report of the 115th ENMC workshop: DM2/PROMM and other myotonic dystrophies. 3rd workshop, 14–16 February 2003, Naarden, the Netherlands. Neuromuscul Disord 13(7–8):589–596CrossRefPubMed

63.

Udd B, Meola G, Krahe R et al (2006) 140th ENMC international workshop: myotonic dystrophy DM2/PROMM and other myotonic dystrophies with guidelines on management. Neuromuscul Disord 16(6):403–413CrossRefPubMed

64.

Vatta M, Mohapatra B, Jimenez S et al (2003) Mutations in Cypher/ZASP in patients with dilated cardiomyopathy and left ventricular non-compaction. J Am Coll Cardiol 42(11):2014–2027CrossRefPubMed

65.

Vihola A, Bassez G, Meola G et al (2003) Histopathological differences of myotonic dystrophy type 1 (DM1) and PROMM/DM2. Neurology 60(11):1854–1857PubMed

66.

Vlasova IA, Tahoe NM, Fan D et al (2008) Conserved GU-rich elements mediate RNA decay by binding to CUG-binding protein 1. Mol Cell 29:263–270CrossRefPubMed

67.

Webster C, Silberstein L, Hays AP, Blau HM (1988) Fast muscle fibers are preferentially affected in duchenne muscular dystrophy. Cell 52(4):503–513CrossRefPubMed

68.

Weiss A, Schiaffino S, Leinwand LA (1999) Comparative sequence analysis of the complete human sarcomeric myosin heavy chain family: implications for functional diversity. J Mol Biol 290(1):61–75CrossRefPubMed

69.

Winter A, Bornemann A (1999) NCAM, vimentin and neonatal myosin heavy chain expression in human muscle diseases. Neuropathol Appl Neurobiol 25(5):417–424CrossRefPubMed

70.

Wu QL, Jha PK, Raychowdhury MK, Du Y, Leavis PC, Sarkar S (1994) Isolation and characterization of human fast skeletal beta troponin T cDNA: comparative sequence analysis of isoforms and insight into the evolution of members of a multigene family. DNA Cell Biol 13(3):217–233CrossRefPubMed

Title: Differences in aberrant expression and splicing of sarcomeric proteins in the myotonic dystrophies DM1 and DM2
Authors: Anna Vihola
Linda L. Bachinski
Mario Sirito
Shodimu-Emmanuel Olufemi
Shohrae Hajibashi
Keith A. Baggerly
Olayinka Raheem
Hannu Haapasalo
Tiina Suominen
Jeanette Holmlund-Hampf
Anders Paetau
Rosanna Cardani
Giovanni Meola
Hannu Kalimo
Lars Edström
Ralf Krahe
Bjarne Udd
Publication date: 01-04-2010
Publisher: Springer-Verlag
Published in: Acta Neuropathologica / Issue 4/2010
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-010-0637-6

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Differences in aberrant expression and splicing of sarcomeric proteins in the myotonic dystrophies DM1 and DM2

Abstract

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 4/2010

Autopsy study of cerebellar degeneration in siblings with ataxia-telangiectasia-like disorder

Loss of murine TDP-43 disrupts motor function and plays an essential role in embryogenesis

Mutant IDH1-specific immunohistochemistry distinguishes diffuse astrocytoma from astrocytosis

Rapid and sensitive assessment of the IDH1 and IDH2 mutation status in cerebral gliomas based on DNA pyrosequencing

Novel myosin heavy chain immunohistochemical double staining developed for the routine diagnostic separation of I, IIA and IIX fibers

Congenital myotonic dystrophy can show congenital fiber type disproportion pathology