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.

A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome

Abstract

Rett syndrome (RTT) is an inherited neurodevelopmental disorder of females that occurs once in 10,000–15,000 births1,2. Affected females develop normally for 6–18 months, but then lose voluntary movements, including speech and hand skills. Most RTT patients are heterozygous for mutations in the X-linked gene MECP2 (refs. 312), encoding a protein that binds to methylated sites in genomic DNA and facilitates gene silencing13,14,15,16,17. Previous work with Mecp2-null embryonic stem cells indicated that MeCP2 is essential for mouse embryogenesis18. Here we generate mice lacking Mecp2 using Cre-loxP technology. Both Mecp2-null mice and mice in which Mecp2 was deleted in brain showed severe neurological symptoms at approximately six weeks of age. Compensation for absence of MeCP2 in other tissues by MeCP1 (refs. 19,20) was not apparent in genetic or biochemical tests. After several months, heterozygous female mice also showed behavioral symptoms. The overlapping delay before symptom onset in humans and mice, despite their profoundly different rates of development, raises the possibility that stability of brain function, not brain development per se, is compromised by the absence of MeCP2.

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: Disruption of mouse Mecp2 using Cre-loxP technology.
Figure 2: Phenotypes of mice with the Mecp2-null mutation.
Figure 3: Effects of Mecp2 deletion on body weight.
Figure 4: Absence of obvious genetic or biochemical interactions between MeCP2 and the methyl-CpG binding repressor Mbd2.

Similar content being viewed by others

References

  1. Rett, V.A. Uber ein eigenartiges hirnatrophisches Syndrom bei Hyperammonamie im Kindesalter. Weiner Medizinische Wochenschrift 37, 723–726 (1966).

    Google Scholar 

  2. Hagberg, B., Aicardi, J., Dias, K. & Ramos, O. A progressive syndrome of autism, dementia, ataxia, and loss of purposeful hand use in girls: Rett's syndrome: report of 35 cases. Ann. Neurol. 14, 471–479 (1983).

    Article  CAS  Google Scholar 

  3. Amir, R.E. et al. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nature Genet. 23, 185–188 (1999).

    Article  CAS  Google Scholar 

  4. Amir, R.E. et al. Influence of mutation type and X chromosome inactivation on Rett syndrome phenotypes. Ann. Neurol. 47, 670–679 (2000).

    Article  CAS  Google Scholar 

  5. Wan, M. et al. Rett syndrome and beyond: recurrent spontaneous and familial MECP2 mutations at CpG hotspots. Am. J. Hum. Genet. 65, 1520–1529 (1999).

    Article  CAS  Google Scholar 

  6. Bienvenu, T. et al. MECP2 mutations account for most cases of typical forms of Rett syndrome. Hum. Mol. Genet. 9, 1377–1284 (2000).

    Article  CAS  Google Scholar 

  7. Cheadle, J.P. et al. Long-read sequence analysis of the MECP2 gene in Rett syndrome patients: correlation of disease severity with mutation type and location. Hum. Mol. Genet. 9, 1119–1129 (2000).

    Article  CAS  Google Scholar 

  8. Hampson, K., Woods, C.G., Latip, F. & Webb, T. Mutations in the MECP2 gene in a cohort of girls with Rett syndrome. J. Med. Genet. 37, 610–612 (2000).

    Article  CAS  Google Scholar 

  9. Huppke, P., Laccone, F., Kramer, N., Engel, W. & Hanefeld, F. Rett syndrome: analysis of MECP2 and clinical characterization of 31 patients. Hum. Mol. Genet. 9, 1369–1375 (2000).

    Article  CAS  Google Scholar 

  10. Obata, K. et al. Mutation analysis of the methyl-CpG-binding protein 2 gene (MECP2) in patients with Rett syndrome. J. Med. Genet. 37, 608–610 (2000).

    Article  CAS  Google Scholar 

  11. Xiang, F. et al. Mutation screening in Rett syndrome patients. J. Med. Genet. 37, 250–255 (2000).

    Article  CAS  Google Scholar 

  12. Buyse, I.M. et al. Diagnostic testing for Rett syndrome by DHPLC and direct sequencing analysis of the MECP2 gene: identification of several novel mutations and polymorphisms. Am. J. Hum. Genet. 67, 1428–1436 (2000).

    Article  CAS  Google Scholar 

  13. Lewis, J.D. et al. Purification, sequence and cellular localization of a novel chromosomal protein that binds to methylated DNA. Cell 69, 905–914 (1992).

    Article  CAS  Google Scholar 

  14. Nan, X., Tate, P., Li, E. & Bird, A.P. DNA methylation specifies chromosomal localization of MeCP2. Mol. Cell. Biol. 16, 414–421 (1996).

    Article  CAS  Google Scholar 

  15. Nan, X., Campoy, J. & Bird, A. MeCP2 is a transcriptional repressor with abundant binding sites in genomic chromatin. Cell 88, 471–481 (1997).

    Article  CAS  Google Scholar 

  16. Nan, X. et al. Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature 393, 386–389 (1998).

    Article  CAS  Google Scholar 

  17. Jones, P.L. et al. Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nature Genet. 19, 187–191 (1998).

    Article  CAS  Google Scholar 

  18. Tate, P., Skarnes, W. & Bird, A. The methyl-CpG binding protein MeCP2 is essential for embryonic development in the mouse. Nature Genet. 12, 205–208 (1996).

    Article  CAS  Google Scholar 

  19. Meehan, R.R., Lewis, J.D., McKay, S., Kleiner, E.L. & Bird, A.P. Identification of a mammalian protein that binds specifically to DNA containing methylated CpGs. Cell 58, 499–507 (1989).

    Article  CAS  Google Scholar 

  20. Ng, H.-H. et al. MBD2 is a transcriptional repressor belonging to the MeCP1 histone deacetylase complex. Nature Genet. 23, 58–61 (1999).

    Article  CAS  Google Scholar 

  21. Sauer, B. & Henderson, N. Site-specific DNA recombination in mammalian cells by the Cre recombinase of bacteriophage P1. Proc. Natl. Acad. Sci. USA 86, 5166–5170 (1988).

    Article  Google Scholar 

  22. 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. 23, 5080–5081 (1995).

    Article  CAS  Google Scholar 

  23. Tronche, F. et al. Disruption of the glucocorticoid receptor gene in the nervous system results in reduced anxiety. Nature Genet. 23, 99–103 (1999).

    Article  CAS  Google Scholar 

  24. Hendrich, B., Guy, J., Ramsahoye, B., Wilson, V.A. & Bird, A. Closely related proteins MBD2 and MBD3 play distinctive but interacting roles in mouse development. Genes Dev. (in press).

  25. Fujita, N. et al. Methylation-mediated transcriptional silencing in euchromatin by methyl-CpG binding protein MBD1 isoforms. Mol. Cell. Biol. 19, 6415–6426 (1999).

    Article  CAS  Google Scholar 

  26. Ng, H.-H., Jeppesen, P. & Bird, A. Active repression of methylated genes by the chromosomal protein MBD1. Mol. Cell. Biol. 20, 1394–1406 (2000).

    Article  CAS  Google Scholar 

  27. Crawley, J.N. et al. Behavioural phenotypes of inbred mouse strains: implications and recommendations for molecular studies. Psychopharmacology 132, 107–124 (1997).

    Article  CAS  Google Scholar 

  28. Chen, R., Akbarian, S., Tudor, M. & Jaenisch, R. Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice. Nature Genet. 27, 327–331 (2001).

    Article  CAS  Google Scholar 

  29. Yusufzai, T.M. & Wolffe, A.P. Functional consequences of Rett syndrome mutations on human MeCP2. Nucleic Acids Res. 28, 4172–4179 (2000).

    Article  CAS  Google Scholar 

  30. Free, A. et al. DNA recognition by the methyl-CpG binding domain of MeCP2. J. Biol. Chem. (in press).

  31. Rogers, D.C. et al. Behavioral and functional analysis of mouse phenotype: SHIRPA, a proposed protocol for comprehensive phenotype assessment. Mamm. Genome 8, 711–713 (1997).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank D. Macleod for monitoring early mouse litters; F. Tronche and G. Schütz for nestin-Cre mice; J. Manson for deleter mice; A.J.H. Smith for ES cells; L. Vizor and J. Noble for phenotypic testing; J. Anthony and I. Davis for photographing mice; A. Greig and J. Davidson for technical assisance; staff of the Anne Walker Building for animal husbandry; A. Maas for instruction on mouse blastocyst injection; and J. Seckl, W. Skarnes, S. Brown, C. Abbott, S. Kriaucionis and J. Selfridge for advice. This work was funded by The Wellcome Trust.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Adrian Bird.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Guy, J., Hendrich, B., Holmes, M. et al. A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome. Nat Genet 27, 322–326 (2001). https://doi.org/10.1038/85899

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/85899

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing