Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Brief Communication
  • Published:

Association of the gene encoding the δ-subunit of the muscle acetylcholine receptor (CHRND) with acquired autoimmune myasthenia gravis

Abstract

The muscle acetylcholine receptor (AChR) is the main target self-antigen in acquired autoimmune myasthenia gravis (MG). Here, we investigated an association of MG with the CHRND gene encoding the δ-subunit of the AChR. Using a microsatellite repeat located in the second intron of the gene, we observed a preferential transmission of the allele 268 in 114 one-generation families with one myasthenic child (Pc=0.0154). This allele was also over-represented in a group of 350 unrelated nonthymoma MG patients (OR=1.78, P=0.038), but not in 84 thymoma patients, compared to 168 healthy controls. Moreover, among nonthymoma patients, those lacking serum anti-titin antibodies appeared to be best associated (OR=2.07, P=0.017). In contrast, there was no distortion in the transmission of a single-nucleotide substitution polymorphisms (SNPs) in the 3′ untranslated region of CHRND nor in that of two SNPs located in the closely linked CHRNG gene, 4.5 kb telomeric to CHRND. The data warrant a detailed investigation of CHRND polymorphism in MG patients.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1

Similar content being viewed by others

Nils Erik Gilhus, Socrates Tzartos, … Jan J. G. M. Verschuuren

References

  1. Engel AG . Myasthenia gravis and myasthenic syndromes. Ann Neurol 1984; 16: 519–534.

    Article  CAS  PubMed  Google Scholar 

  2. Drachman DB . Myasthenia gravis. N Engl J Med 1994; 330: 1797–1810.

    Article  CAS  PubMed  Google Scholar 

  3. Vincent A, Palace J, Hilton-Jones D . Myasthenia gravis. Lancet 2001; 357: 2122–2128.

    Article  CAS  PubMed  Google Scholar 

  4. Patrick J, Lindstrom J . Autoimmune response to acetylcholine receptor. Science 1973; 180: 871–872.

    Article  CAS  PubMed  Google Scholar 

  5. Tzartos SJ, Barkas T, Cung MT et al. Anatomy of the antigenic structure of a large membrane autoantigen, the muscle-type nicotinic acetylcholine receptor. Immunol Rev 1998; 163: 89–120.

    Article  CAS  PubMed  Google Scholar 

  6. Willcox N . Myasthenia gravis. Curr Opin Immunol 1993; 5: 910–917.

    Article  CAS  PubMed  Google Scholar 

  7. Giraud M, Beaurain G, Yamamoto AM et al. Linkage of HLA to myasthenia gravis and genetic heterogeneity depending on anti-titin antibodies. Neurology 2001; 57: 1555–1560.

    Article  CAS  PubMed  Google Scholar 

  8. Garchon HJ, Djabiri F, Viard JP, Gajdos P, Bach JF . Involvement of human muscle acetylcholine receptor alpha-subunit gene (CHRNA) in susceptibility to myasthenia gravis. Proc Natl Acad Sci USA 1994; 91: 4668–4672.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Heckmann JM, Morrison KE, Emeryk-Szajewska B et al. Human muscle acetylcholine receptor alpha-subunit gene (CHRNA1) association with autoimmune myasthenia gravis in black, mixed-ancestry and Caucasian subjects. J Autoimmun 1996; 9: 175–180.

    Article  CAS  PubMed  Google Scholar 

  10. Protti MP, Manfredi AA, Wu XD, Moiola L, Howard Jr JF, Conti-Tronconi BM . Myasthenia gravis. T epitopes on the delta subunit of human muscle acetylcholine receptor. J Immunol 1991; 146: 2253–2261.

    CAS  PubMed  Google Scholar 

  11. Manfredi AA, Protti MP, Dalton MW, Howard Jr JF, Conti-Tronconi BM . T helper cell recognition of muscle acetylcholine receptor in myasthenia gravis. Epitopes on the gamma and delta subunits. J Clin Invest 1993; 92: 1055–1067.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Wang WZ, Fredrikson S, Qiao J, Osterman PO, Link H . The B-cell repertoire in myasthenia gravis includes all four acetylcholine receptor subunits. Acta Neurol Scand 1998; 98: 422–426.

    Article  CAS  PubMed  Google Scholar 

  13. Ramanathan VK, Hall ZW . Altered glycosylation sites of the delta subunit of the acetylcholine receptor (AChR) reduce alpha delta association and receptor assembly. J Biol Chem 1999; 274: 20513–20520.

    Article  CAS  PubMed  Google Scholar 

  14. Navaneetham D, Penn AS, Howard Jr JF, Conti-Fine BM . Human thymuses express incomplete sets of muscle acetylcholine receptor subunit transcripts that seldom include the delta subunit. Muscle Nerve 2001; 24: 203–210.

    Article  CAS  PubMed  Google Scholar 

  15. Hohlfeld R, Wekerle H . The role of the thymus in myasthenia gravis. Adv Neuroimmunol 1994; 4: 373–386.

    Article  CAS  PubMed  Google Scholar 

  16. Quiram PA, Ohno K, Milone M et al. Mutation causing congenital myasthenia reveals acetylcholine receptor beta/delta subunit interaction essential for assembly. J Clin Invest 1999; 104: 1403–1410.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Brownlow S, Webster R, Croxen R et al. Acetylcholine receptor delta subunit mutations underlie a fast-channel myasthenic syndrome and arthrogryposis multiplex congenita. J Clin Invest 2001; 108: 125–130.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Landa BL, Reynolds JE, Beeson D, Diehl SR . Dinucleotide repeat polymorphism at the CHRND locus. Hum Mol Genet 1994; 3: 1445.

    Article  CAS  PubMed  Google Scholar 

  19. Spielman RS, McGinnis RE, Ewens WJ . Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet 1993; 52: 506–516.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Kruglyak L, Daly MJ, Reeve-Daly MP, Lander ES . Parametric and nonparametric linkage analysis: a unified multipoint approach. Am J Hum Genet 1996; 58: 1347–1363.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Sham PC, Curtis D . An extended transmission/disequilibrium test (TDT) for multi-allele marker loci. Ann Hum Genet 1995; 59: 323–336.

    Article  CAS  PubMed  Google Scholar 

  22. Yamamoto AM, Gajdos P, Eymard B et al. Anti-titin antibodies in myasthenia gravis: tight association with thymoma and heterogeneity of nonthymoma patients. Arch Neurol 2001; 58: 885–890.

    Article  CAS  PubMed  Google Scholar 

  23. Wells RD . Unusual DNA structures. J Biol Chem 1988; 263: 1095–1098.

    CAS  PubMed  Google Scholar 

  24. Rothenburg S, Koch-Nolte F, Rich A, Haag F . A polymorphic dinucleotide repeat in the rat nucleolin gene forms Z-DNA and inhibits promoter activity. Proc Natl Acad Sci USA 2001; 98: 8985–8990.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Hill WG, Weir BS . Maximum-likelihood estimation of gene location by linkage disequilibrium. Am J Hum Genet 1994; 54: 705–714.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Excoffier L, Slatkin M . Maximum-likelihood estimation of molecular haplotype frequencies in a diploid population. Mol Biol Evol 1995; 12: 921–927.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was funded by INSERM (Institut National de la Santé et de la Recherche Médicale) and by the Association Française contre les Myopathies. MG is a fellow of the Ministère de la Recherche. We are most grateful to Ms Claudia de Toma (Fondation Jean Dausset – Centre d’Etude du Polymorphisme Humain, Paris) for her generous gift of control DNA samples. We thank Guy Fluteau for his technical help.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to H-J Garchon.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Giraud, M., Eymard, B., Tranchant, C. et al. Association of the gene encoding the δ-subunit of the muscle acetylcholine receptor (CHRND) with acquired autoimmune myasthenia gravis. Genes Immun 5, 80–83 (2004). https://doi.org/10.1038/sj.gene.6364041

Download citation

  • Received:

  • Revised:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gene.6364041

Keywords

This article is cited by

Search

Quick links