Skip to main content
SpringerLink
Log in

MBNL1 gene variants as modifiers of disease severity in myotonic dystrophy type 1

  • Original Communication
  • Published:
Journal of Neurology Aims and scope Submit manuscript

Abstract

Myotonic dystrophy type 1 (DM1) is a multisystemic autosomal dominant disorder characterized by a highly variable phenotype and caused by an unstable CTG repeat expansion in the 3′ untranslated region of the dystrophia myotonica protein kinase (DMPK) gene. Longer CTG repeat expansions often correlate with an anticipated age at onset and CTG repeat number may account for 45–60 % of the variance in disease severity. In order to search for candidate genes that could act as modifiers of disease severity, we studied the association between Muscleblind-like protein-1 (MBNL1) gene polymorphisms and the DM1 phenotype. In a group of 301 patients diagnosed with DM1 based on clinical symptoms, diagnosis was confirmed by molecular analysis of the DMPK gene. Patients were divided into four subtypes. The first subtype corresponded to asymptomatic patients or those with a mild phenotype, the second included those with a classic phenotype, the third concerned childhood onset, and the fourth corresponded to the congenital form of DM1. Three SNPs located in the MBNL1 gene promoter, rs323622, rs17283597, and rs17433672, were studied. Case–control analysis revealed that allele frequencies for the latter two were significantly associated with DM1 (p = 0.037 and p = 0.020). Multivariate linear regression analysis using phenotype as the dependent variable demonstrated that the TT genotype of the third SNP, rs323622, was associated with a more severe phenotype (p = 0.0034) and accounted for 1.88 % of the variance in disease severity. We report the association of several genetic variants of the MBNL1 gene with DM1 or with the severity of the disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Harper PS (2001) Myotonic dystrophy. In: 3rd edn. WB Saunders, London

  2. Brook JD, Mc Currach 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):799–808

    Article  PubMed  CAS  Google Scholar 

  3. Harper PS (2004) Myotonic dystrophy: present management, future therapy. Oxford University Press, Oxford

    Google Scholar 

  4. Turner C, Hilton-Jones D (2010) The myotonic dystrophies: diagnosis and management. J Neurol Neurosurg Psychiatry 81:358–367

    Article  PubMed  Google Scholar 

  5. Arsenault ME, Prevost C, Lescault A et al (2006) Clinical characteristics of myotonic dystrophy type 1 patients with small CTG expansions. Neurology 66(8):1248–1250

    Article  PubMed  Google Scholar 

  6. Steyaert J, Umans S, Willekens D et al (1997) A study of the cognitive and psychosocial profile in 16 children with congenital or juvenile myotonic dystrophy. Clin Genet 52:135–141

    Article  PubMed  CAS  Google Scholar 

  7. Harley HG, Rundle SA, MacMillan JC et al (1993) Size of the unstable CTG repeat sequence in relation to phenotype and parental transmission in myotonic dystrophy. Am J Hum Genet 52(6):1164–1174

    PubMed  CAS  Google Scholar 

  8. Novelli G, Gennarelli M, Menegazzo E et al (1993) (CTG)n triplet mutation and phenotype manifestation in myotonic dystrophy patients. Biochem Med Metab Biol 50:85–92

    Article  PubMed  CAS  Google Scholar 

  9. Hamshere MG, Harley HG, Harper PS, Brook JD, Brookfield JF (1999) Myotonic dystrophy: the correlation of the CTG repeat length in leukocytes with age at onset is significant only for patients with small expansions. J Med Genet 36(1):59–61

    PubMed  CAS  Google Scholar 

  10. Lavedan C, Hofmann-Radvanyi H, Shelbourne P et al (1993) Myotonic dystrophy: size- and sex-dependent dynamics of CTG meiotic instability, and somatic mosaicism. Am J Hum Genet 52:875–883

    PubMed  CAS  Google Scholar 

  11. Morales F, Couto JM, Higham CF et al (2012) Somatic instability of the expanded CTG triplet repeat in myotonic dystrophy type1 is a heritable quantitative trait and modifier of disease severity. Hum Mol Genet 21(16):3558–3567

    Article  PubMed  CAS  Google Scholar 

  12. Rinaldi F, Botta A, Vallo L et al (2008) Analysis of single-nucleotide polymorphisms (SNPs) of the small-conductance calcium activated potassium channel (SK3) gene as genetic modifier of the cardiac phenotype in myotonic dystrophy type1 patients. Acta Myologica 27:82–89

    PubMed  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  14. Osborne RJ, Thornton CA (2006) RNA-dominant diseases. Hum Mol Genet 15:R162–R169

    Article  PubMed  CAS  Google Scholar 

  15. Charlet-B N, Savkur R, 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):45–53

    Article  PubMed  CAS  Google Scholar 

  16. Suenaga K, Lee KY, Nakamori M et al (2012) Muscleblind-like1 knockout mice reveal novel splicing defects in the myotonic dystrophy brain. PLoS ONE 7(3):e33218

    Article  PubMed  CAS  Google Scholar 

  17. Sergeant N, Sablonnière B, Schraen-Maschke S et al (2001) Dysregulation of human brain microtubule-associated tau mRNA maturation in myotonic dystrophy type 1. Hum Mol Genet 10(19):2143–2155

    Article  PubMed  CAS  Google Scholar 

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

    Article  Google Scholar 

  19. Barett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21:263–265

    Article  Google Scholar 

  20. Sham PC, Curtis D (1995) Monte Carlo tests for associations between disease and alleles at highly polymorphic loci. Ann Hum Genet 59:97–105

    Article  PubMed  CAS  Google Scholar 

  21. Tregouet DA, Garelle V (2007) A new JAVA interface implementation of THESIAS: testing haplotype effects in association studies. Bioinformatics 23(8):1038–1039

    Article  PubMed  CAS  Google Scholar 

  22. Mathieu J, Allard P, Potvin L, Prevost C, Begin P (1999) A 10-year study of mortality in a cohort of patients with myotonic dystrophy. Neurology 52(8):1658–1662

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  24. Flicek P, Aken BL, Beal K et al (2008) Ensembl. Nucl Acids Res. 36(Database issue):D707–714

    PubMed  CAS  Google Scholar 

  25. 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. Proc Natl Acad Sci USA 103:11748–11753

    Article  PubMed  CAS  Google Scholar 

  26. Kino Y, Mori D, Oma Y, Takeshita Y, Sasagawa N, Ishiura S (2004) Muscleblind protein, MBNL1/EXP, binds to CHHG repeats. Hum Mol Genet 13:495–507

    Article  PubMed  CAS  Google Scholar 

  27. Yadava RS, Frenzel-McCardell CD, Yu Q et al (2008) RNA toxicity in myotonic dystrophy induces NKX2-5 expression. Nat Genet 40:61–68

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We are grateful to Patrick Devos and to Kathy Dupont for their expert technical assistance. This work was supported by the Centre Régional et Universitaire de Lille (CHRU), The University of Lille Nord de France, INSERM U837, the Association Française contre les myopathies Grants 14269 and 15047, the Centre National de la Recherche Scientifique, the Institut National pour la Santé et la Recherche Médicale, and the Agence Nationale de Recherche NeurospliceTau BLAN 111401.

Conflicts of interest

The authors disclose any potential financial conflicts of interest.

Ethical standard

This study has been approved by the local ethical committee and has therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki.

Author information

Authors and Affiliations

  1. INSERM UMR837, Alzheimer and Tauopathies, University Lille-Nord de France, USDL, IMPRT, Jean-Pierre Aubert Research Center, Batiment Biserte, 1, Place de Verdun, 59045, Lille, France

    Vincent Huin, Susanna Schraen-Maschke, Claire-Marie Dhaenens, Nicolas Sergeant, Luc Buée & Bernard Sablonnière

  2. EA2694, Lille University Medical Center, Lille, France

    Francis Vasseur

  3. Department of Molecular Biology, Lille University Medical Center, Lille, France

    Susanna Schraen-Maschke, Claire-Marie Dhaenens, Patrick Devos, Kathy Dupont & Bernard Sablonnière

  4. Department of Clinical Neurology and Center for Rare Neuromuscular Diseases, Lille University Medical Center, Lille, France

    Arnaud Lacour

  5. University Versailles-Saint Quentin en Yvelines, AP-HP, Biochemistry and Molecular Genetics Laboratory, Hôpital Ambroise Paré, Boulogne, France

    Hélène Hofmann-Radvanyi

Authors
  1. Vincent Huin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Francis Vasseur
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Susanna Schraen-Maschke
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Claire-Marie Dhaenens
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Patrick Devos
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kathy Dupont
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Nicolas Sergeant
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Luc Buée
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Arnaud Lacour
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hélène Hofmann-Radvanyi
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Bernard Sablonnière
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bernard Sablonnière.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Huin, V., Vasseur, F., Schraen-Maschke, S. et al. MBNL1 gene variants as modifiers of disease severity in myotonic dystrophy type 1. J Neurol 260, 998–1003 (2013). https://doi.org/10.1007/s00415-012-6740-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00415-012-6740-y

Keywords

Search

Navigation