Mutation in ε-Sarcoglycan Induces a Myoclonus-Dystonia Syndrome-Like Movement Disorder in Mice


Myoclonus dystonia syndrome (MDS) is an inherited movement disorder, and most MDS-related mutations have so far been found in the ε-sarcoglycan (SGCE) coding gene. By generating SGCE-knockout (KO) and human 237 C > T mutation knock-in (KI) mice, we showed here that both KO and KI mice exerted typical movement defects similar to those of MDS patients. SGCE promoted filopodia development in vitro and inhibited excitatory synapse formation both in vivo and in vitro. Loss of function of SGCE leading to excessive excitatory synapses that may ultimately contribute to MDS pathology. Indeed, using a zebrafish MDS model, we found that among 1700 screened chemical compounds, Vigabatrin was the most potent in readily reversing MDS symptoms of mouse disease models. Our study strengthens the notion that mutations of SGCE lead to MDS and most likely, SGCE functions to brake synaptogenesis in the CNS.

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  1. 1.

    Kinugawa K, Vidailhet M, Clot F, Apartis E, Grabli D, Roze E. Myoclonus-dystonia: an update. Mov Disord 2009, 24: 479–489.

    Article  Google Scholar 

  2. 2.

    Phukan J, Albanese A, Gasser T, Warner T. Primary dystonia and dystonia-plus syndromes: clinical characteristics, diagnosis, and pathogenesis. Lancet Neurol 2011, 10: 1074–1085.

    Article  Google Scholar 

  3. 3.

    Popa T, Milani P, Richard A, Hubsch C, Brochard V, Tranchant C et al. The neurophysiological features of myoclonus-dystonia and differentiation from other dystonias. JAMA Neurol 2014, 71: 612–619.

    Article  Google Scholar 

  4. 4.

    Roze E, Apartis E, Clot F, Dorison N, Thobois S, Guyant-Marechal L, et al. Myoclonus-dystonia: clinical and electrophysiologic pattern related to SGCE mutations. Neurology 2008, 70: 1010–1016.

    CAS  Article  Google Scholar 

  5. 5.

    Asmus F, Gasser T. Inherited myoclonus-dystonia. Adv Neurol 2004, 94: 113–119.

    PubMed  Google Scholar 

  6. 6.

    Grabowski M, Zimprich A, Lorenz-Depiereux B, Kalscheuer V, Asmus F, Gasser T, et al. The epsilon-sarcoglycan gene (SGCE), mutated in myoclonus-dystonia syndrome, is maternally imprinted. Eur J Hum Genet 2003, 11: 138–144.

    CAS  Article  Google Scholar 

  7. 7.

    Zimprich A, Grabowski M, Asmus F, Naumann M, Berg D, Bertram M, et al. Mutations in the gene encoding epsilon-sarcoglycan cause myoclonus-dystonia syndrome. Nat Genet 2001, 29: 66–69.

    CAS  Article  Google Scholar 

  8. 8.

    Yan H, Guan X, Wang L, Tan J, Wang G, An Y, et al. A point mutation in epsilon-sarcoglycan induces inherited myoclonus dystonia syndrome in a Chinese family. Int J Clin Exp Med 2013, 6: 289–293.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Peall KJ, Kurian MA, Wardle M, Waite AJ, Hedderly T, Lin JP, et al. SGCE and myoclonus dystonia: motor characteristics, diagnostic criteria and clinical predictors of genotype. J Neurol 2014, 261: 2296–2304.

    CAS  Article  Google Scholar 

  10. 10.

    Rachad L, El Kadmiri N, Slassi I, El Otmani H, Nadifi S. Genetic aspects of myoclonus-dystonia syndrome (MDS). Mol Neurobiol 2016: 939–942.

  11. 11.

    Sun X, Wu Y, Gu M, Liu Z, Ma Y, Li J, et al. Selective filtering defect at the axon initial segment in Alzheimer's disease mouse models. Proc Natl Acad Sci U S A 2014, 111: 14271–14276.

    CAS  Article  Google Scholar 

  12. 12.

    Li JY, Cunic DI, Paradiso G, Gunraj C, Pal PK, Lang AE, et al. Electrophysiological features of myoclonus-dystonia. Mov Disord 2008, 23: 2055–2061.

    CAS  Article  Google Scholar 

  13. 13.

    Hjermind LE, Vissing J, Asmus F, Krag T, Lochmuller H, Walter MC, et al. No muscle involvement in myoclonus-dystonia caused by epsilon-sarcoglycan gene mutations. Eur J Neurol 2008, 15: 525–529.

    CAS  Article  Google Scholar 

  14. 14.

    Ritz K, van Schaik BD, Jakobs ME, van Kampen AH, Aronica E, Tijssen MA, et al. SGCE isoform characterization and expression in human brain: implications for myoclonus-dystonia pathogenesis? Eur J Hum Genet 2011, 19: 438–444.

    CAS  Article  Google Scholar 

  15. 15.

    Waite A, Brown SC, Blake DJ. The dystrophin-glycoprotein complex in brain development and disease. Trends Neurosci 2012, 35: 487–496.

    CAS  Article  Google Scholar 

  16. 16.

    Yokoi F, Dang MT, Li J, Li Y. Myoclonus, motor deficits, alterations in emotional responses and monoamine metabolism in epsilon-sarcoglycan deficient mice. J Biochem 2006, 140: 141–146.

    CAS  Article  Google Scholar 

  17. 17.

    Rangel-Barajas C, Coronel I, Floran B. Dopamine receptors and neurodegeneration. Aging Dis 2015, 6: 349–368.

    PubMed  Google Scholar 

  18. 18.

    Hedrich K, Meyer EM, Schule B, Kock N, de Carvalho Aguiar P, Wiegers K, et al. Myoclonus-dystonia: detection of novel, recurrent, and de novo SGCE mutations. Neurology 2004, 62:1229–1231.

    CAS  Article  Google Scholar 

  19. 19.

    Yokoi F, Dang MT, Mitsui S, Li Y. Exclusive paternal expression and novel alternatively spliced variants of epsilon-sarcoglycan mRNA in mouse brain. FEBS Lett 2005, 579: 4822–4828.

    CAS  Article  Google Scholar 

  20. 20.

    Lancioni A, Rotundo IL, Kobayashi YM, D'Orsi L, Aurino S, Nigro G, et al. Combined deficiency of alpha and epsilon sarcoglycan disrupts the cardiac dystrophin complex. Hum Mol Genet 2011, 20: 4644–4654.

    CAS  Article  Google Scholar 

  21. 21.

    Schwenk F, Baron U, Rajewsky K. A cre-transgenic mouse strain for the ubiquitous deletion of loxP-flanked gene segments including deletion in germ cells. Nucleic Acids Res 1995, 23: 5080–5081.

    CAS  Article  Google Scholar 

  22. 22.

    Waite A, De Rosa MC, Brancaccio A, Blake DJ. A gain-of-glycosylation mutation associated with myoclonus-dystonia syndrome affects trafficking and processing of mouse epsilon-sarcoglycan in the late secretory pathway. Hum Mutat 2011, 32:1246–1258.

    CAS  Article  Google Scholar 

  23. 23.

    Peall KJ, Waite AJ, Blake DJ, Owen MJ, Morris HR: Psychiatric disorders, myoclonus dystonia, and the epsilon-sarcoglycan gene: a systematic review. Mov Disord 2011, 26:1939–1942.

    Article  Google Scholar 

  24. 24.

    Asmus F, Hjermind LE, Dupont E, Wagenstaller J, Haberlandt E, Munz M, et al. Genomic deletion size at the epsilon-sarcoglycan locus determines the clinical phenotype. Brain 2007, 130: 2736–2745.

    Article  Google Scholar 

  25. 25.

    Kaplan JS, Mohr C, Rossi DJ. Opposite actions of alcohol on tonic GABA(A) receptor currents mediated by nNOS and PKC activity. Nat Neurosci 2013, 16:1783–1793.

    CAS  Article  Google Scholar 

  26. 26.

    Yoshihara Y, De Roo M, Muller D. Dendritic spine formation and stabilization. Curr Opin Neurobiol 2009, 19:146–153.

    CAS  Article  Google Scholar 

  27. 27.

    Esapa CT, Waite A, Locke M, Benson MA, Kraus M, McIlhinney RA, et al. SGCE missense mutations that cause myoclonus-dystonia syndrome impair epsilon-sarcoglycan trafficking to the plasma membrane: modulation by ubiquitination and torsinA. Hum Mol Genet 2007, 16: 327–342.

    CAS  Article  Google Scholar 

  28. 28.

    Yokoi F, Dang MT, Yang G, Li J, Doroodchi A, Zhou T, et al. Abnormal nuclear envelope in the cerebellar Purkinje cells and impaired motor learning in DYT11 myoclonus-dystonia mouse models. Behav Brain Res 2012, 227: 12–20.

    CAS  Article  Google Scholar 

  29. 29.

    Caviness JN. Pathophysiology and treatment of myoclonus. Neurol Clin 2009, 27: 757–777, vii.

    Google Scholar 

  30. 30.

    Cif L, Valente EM, Hemm S, Coubes C, Vayssiere N, Serrat S, et al. Deep brain stimulation in myoclonus-dystonia syndrome. Mov Disord 2004, 19: 724–727.

    Article  Google Scholar 

  31. 31.

    Kurtis MM, San Luciano M, Yu Q, Goodman RR, Ford B, Raymond D, et al. Clinical and neurophysiological improvement of SGCE myoclonus-dystonia with GPi deep brain stimulation. Clin Neurol Neurosurg 2010, 112: 149–152.

    Article  Google Scholar 

  32. 32.

    Azoulay-Zyss J, Roze E, Welter ML, Navarro S, Yelnik J, Clot F, et al. Bilateral deep brain stimulation of the pallidum for myoclonus-dystonia due to epsilon-sarcoglycan mutations: a pilot study. Arch Neurol 2011, 68: 94–98.

    Article  Google Scholar 

  33. 33.

    Ramdhani RA, Frucht SJ, Behnegar A, Kopell BH. Improvement of isolated myoclonus phenotype in myoclonus dystonia after pallidal deep brain stimulation. Tremor Other Hyperkinet Mov (N Y) 2016, 6: 369.

    Article  Google Scholar 

  34. 34.

    Rocha H, Linhares P, Chamadoira C, Rosas MJ, Vaz R. Early deep brain stimulation in patients with myoclonus-dystonia syndrome. J Clin Neurosci 2016, 27:17–21.

    Article  Google Scholar 

  35. 35.

    Luciano AY, Jinnah HA, Pfeiffer RF, Truong DD, Nance MA, LeDoux MS. Treatment of myoclonus-dystonia syndrome with tetrabenazine. Parkinsonism Relat Disord 2014, 20: 1423–1426.

    Article  Google Scholar 

  36. 36.

    Hess CW, Raymond D, Aguiar Pde C, Frucht S, Shriberg J, Heiman GA, et al. Myoclonus-dystonia, obsessive-compulsive disorder, and alcohol dependence in SGCE mutation carriers. Neurology 2007, 68: 522–524.

    CAS  Article  Google Scholar 

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This work was supported by National Natural Science Foundation of China (31630028, 91632305, and 91632303), the Fund for Distinguished Young Scholars of National Natural Science Foundation of China (81425009 and 81425007), the National Basic Science Research Program of China (2012CB933900 and 2015CB755600), the Strategic Priority Research Program (B) of China (XDB02050500).

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Correspondence to Xuliang Deng or Yan Zhang.

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Li, J., Liu, Y., Li, Q. et al. Mutation in ε-Sarcoglycan Induces a Myoclonus-Dystonia Syndrome-Like Movement Disorder in Mice. Neurosci. Bull. (2020).

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  • SGCE
  • MDS
  • Filopodia
  • Synapse
  • Excitability