Letter | Published:

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

Nature Genetics volume 27, pages 322326 (2001) | Download Citation

Subjects

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. 3,​4,​5,​6,​7,​8,​9,​10,​11,​12), 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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

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

  2. 2.

    , , & 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).

  3. 3.

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

  4. 4.

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

  5. 5.

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

  6. 6.

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

  7. 7.

    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).

  8. 8.

    , , & Mutations in the MECP2 gene in a cohort of girls with Rett syndrome. J. Med. Genet. 37, 610–612 (2000).

  9. 9.

    , , , & Rett syndrome: analysis of MECP2 and clinical characterization of 31 patients. Hum. Mol. Genet. 9, 1369–1375 (2000).

  10. 10.

    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).

  11. 11.

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

  12. 12.

    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).

  13. 13.

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

  14. 14.

    , , & DNA methylation specifies chromosomal localization of MeCP2. Mol. Cell. Biol. 16, 414–421 (1996).

  15. 15.

    , & MeCP2 is a transcriptional repressor with abundant binding sites in genomic chromatin. Cell 88, 471–481 (1997).

  16. 16.

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

  17. 17.

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

  18. 18.

    , & The methyl-CpG binding protein MeCP2 is essential for embryonic development in the mouse. Nature Genet. 12, 205–208 (1996).

  19. 19.

    , , , & Identification of a mammalian protein that binds specifically to DNA containing methylated CpGs. Cell 58, 499–507 (1989).

  20. 20.

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

  21. 21.

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

  22. 22.

    , & 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).

  23. 23.

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

  24. 24.

    , , , & Closely related proteins MBD2 and MBD3 play distinctive but interacting roles in mouse development. Genes Dev. (in press).

  25. 25.

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

  26. 26.

    , & Active repression of methylated genes by the chromosomal protein MBD1. Mol. Cell. Biol. 20, 1394–1406 (2000).

  27. 27.

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

  28. 28.

    , , & Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice. Nature Genet. 27, 327–331 (2001).

  29. 29.

    & Functional consequences of Rett syndrome mutations on human MeCP2. Nucleic Acids Res. 28, 4172–4179 (2000).

  30. 30.

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

  31. 31.

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

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

Affiliations

  1. Wellcome Centre for Cell Biology, Institute of Cell and Molecular Biology, University of Edinburgh, The King's Buildings, Edinburgh, UK.

    • Jacky Guy
    • , Brian Hendrich
    •  & Adrian Bird
  2. Department of Clinical Neurosciences, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Edinburgh, UK.

    • Megan Holmes
  3. St Bartholomews and the Royal London School of Medicine and Dentistry, Queen Mary and Westfield College, The Institute of Pathology, The Royal London Hospital, Whitechapel, London, UK.

    • Joanne E. Martin

Authors

  1. Search for Jacky Guy in:

  2. Search for Brian Hendrich in:

  3. Search for Megan Holmes in:

  4. Search for Joanne E. Martin in:

  5. Search for Adrian Bird in:

Corresponding author

Correspondence to Adrian Bird.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/85899

Further reading