Human Genetics

, Volume 116, Issue 1, pp 91–104

The impact of MECP2 mutations in the expression patterns of Rett syndrome patients

Authors

  • Esteban Ballestar
    • Cancer Epigenetics Laboratory, Molecular Pathology ProgrammeSpanish National Cancer Centre (CNIO)
  • Santiago Ropero
    • Cancer Epigenetics Laboratory, Molecular Pathology ProgrammeSpanish National Cancer Centre (CNIO)
  • Miguel Alaminos
    • Cancer Epigenetics Laboratory, Molecular Pathology ProgrammeSpanish National Cancer Centre (CNIO)
  • Judith Armstrong
    • Genetics SectionUniversity Hospital Sant Joan de Deu
  • Fernando Setien
    • Cancer Epigenetics Laboratory, Molecular Pathology ProgrammeSpanish National Cancer Centre (CNIO)
  • Ruben Agrelo
    • Cancer Epigenetics Laboratory, Molecular Pathology ProgrammeSpanish National Cancer Centre (CNIO)
  • Mario F. Fraga
    • Cancer Epigenetics Laboratory, Molecular Pathology ProgrammeSpanish National Cancer Centre (CNIO)
  • Michel Herranz
    • Cancer Epigenetics Laboratory, Molecular Pathology ProgrammeSpanish National Cancer Centre (CNIO)
  • Sonia Avila
    • Cancer Epigenetics Laboratory, Molecular Pathology ProgrammeSpanish National Cancer Centre (CNIO)
  • Mercedes Pineda
    • Neurology ServiceUniversity Hospital Sant Joan de Deu
  • Eugenia Monros
    • Genetics SectionUniversity Hospital Sant Joan de Deu
    • Cancer Epigenetics Laboratory, Molecular Pathology ProgrammeSpanish National Cancer Centre (CNIO)
Original Investigation

DOI: 10.1007/s00439-004-1200-0

Cite this article as:
Ballestar, E., Ropero, S., Alaminos, M. et al. Hum Genet (2005) 116: 91. doi:10.1007/s00439-004-1200-0

Abstract

Rett syndrome (RTT), the second most common cause of mental retardation in females, has been associated with mutations in MeCP2, the archetypical member of the methyl-CpG binding domain (MBD) family of proteins. MeCP2 additionally possesses a transcriptional repression domain (TRD). We have compared the gene expression profiles of RTT- and normal female-derived lymphoblastoid cells by using cDNA microarrays. Clustering analysis allowed the classification of RTT patients according to the localization of the MeCP2 mutation (MBD or TRD) and those with clinically diagnosed RTT but without detectable MeCP2 mutations. Numerous genes were observed to be overexpressed in RTT patients compared with control samples, including excellent candidate genes for neurodevelopmental disease. Chromatin immunoprecipitation analysis confirmed that binding of MeCP2 to corresponding promoter CpG islands was lost in RTT-derived cells harboring a mutation in the region of the MECP2 gene encoding the MBD. Bisulfite genomic sequencing demonstrated that the majority of MeCP2 binding occurred in DNA sequences with methylation-associated silencing. Most importantly, the finding that these genes are also methylated and bound by MeCP2 in neuron-related cells suggests a role in this neurodevelopmental disease. Our results provide new data of the underlying mechanisms of RTT and unveil novel targets of MeCP2-mediated gene repression.

Copyright information

© Springer-Verlag 2004