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Interaction between chromatin proteins MECP2 and ATRX is disrupted by mutations that cause inherited mental

Xinsheng Nan1, Jianghui Hou, Alan Maclean

  • 1Wellcome Trust Centre for Cell Biology, University of Edinburgh, The King's Buildings, Edinburgh EH9 3JR, United Kingdom. xinsheng.nan@csc.mrc.ac.uk

Proceedings of the National Academy of Sciences of the United States of America
|February 14, 2007
PubMed

Insights

Mutations in methyl-CpG-binding protein 2 (MECP2) cause Rett syndrome. This study reveals MECP2 interacts with ATRX, and disrupted interaction contributes to mental retardation and neurological disorders.

Area of Science:

  • Neurogenetics
  • Molecular Biology
  • Epigenetics

Background:

  • Mutations in the methyl-CpG-binding protein 2 (MECP2) gene are linked to Rett syndrome and X-linked mental retardation (XLMR).
  • ATRX syndrome, characterized by alpha-thalassemia and mental retardation, is caused by mutations in the ATRX gene, which encodes a SWI2/SNF2 DNA helicase/ATPase.

Purpose of the Study:

  • To investigate the interaction between MECP2 and ATRX.
  • To determine the functional consequences of this interaction in the context of neurological disorders.

Main Methods:

  • Co-immunoprecipitation assays to assess protein-protein interactions.
  • Live-cell imaging to observe protein localization in mouse cells.
  • Analysis of Mecp2-null mouse neurons to evaluate ATRX localization.

Main Results:

  • MeCP2 interacts with ATRX, recruiting the ATRX helicase domain to heterochromatic foci in a DNA methylation-dependent manner.
  • ATRX localization is disrupted in neurons lacking Mecp2.
  • Specific MECP2 mutations associated with Rett syndrome and XLMR impair the MeCP2-ATRX interaction without affecting DNA binding.

Conclusions:

  • The interaction between MECP2 and ATRX is crucial for proper protein localization and function.
  • Disruption of the MECP2-ATRX interaction may underlie the pathogenesis of mental retardation in MECP2-associated disorders.

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