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An AT-hook domain in MeCP2 determines the clinical course of Rett syndrome and related disorders.

Mutations in the X-linked MECP2 cause Rett syndrome, a devastating neurological disorder typified by a period of apparently normal development followed by loss of cognitive and psychomotor skills. Data from rare male patients suggest symptom onset and severity can be influenced by the location of the mutation, with amino acids 270 and 273 marking the difference between neonatal encephalopathy and death, on the one hand, and survival with deficits on the other. We therefore generated two mouse models expressing either MeCP2-R270X or MeCP2-G273X. The mice developed phenotypes at strikingly different rates and showed differential ATRX nuclear localization within the nervous system, over time, coinciding with phenotypic progression. We discovered that MeCP2 contains three AT-hook-like domains over a stretch of 250 amino acids, like HMGA DNA-bending proteins; one conserved AT-hook is disrupted in MeCP2-R270X, lending further support to the notion that one of MeCP2's key functions is to alter chromatin structure.

Pubmed ID: 23452848

Authors

  • Baker SA
  • Chen L
  • Wilkins AD
  • Yu P
  • Lichtarge O
  • Zoghbi HY

Journal

Cell

Publication Data

February 28, 2013

Associated Grants

  • Agency: NINDS NIH HHS, Id: F30 NS066527
  • Agency: NINDS NIH HHS, Id: F30NS066527
  • Agency: NICHD NIH HHS, Id: HD024064
  • Agency: NINDS NIH HHS, Id: NS053862
  • Agency: NICHD NIH HHS, Id: P30 HD024064
  • Agency: NIGMS NIH HHS, Id: R01 GM079656
  • Agency: NINDS NIH HHS, Id: R01 NS057819
  • Agency: Howard Hughes Medical Institute, Id:
  • Agency: Howard Hughes Medical Institute, Id:

Mesh Terms

  • Amino Acid Sequence
  • Animals
  • DNA Helicases
  • Disease Models, Animal
  • Female
  • Heterochromatin
  • Male
  • Methyl-CpG-Binding Protein 2
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Molecular Sequence Data
  • Nuclear Proteins
  • Protein Structure, Tertiary
  • Rett Syndrome
  • Sequence Alignment
  • Transcription, Genetic