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Rett Syndrome MECP

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					                The role of
        Methyl-CpG Binding Protein 2
             in Rett Syndrome
                                              Jessica Connor


http://www.nih.gov/news/research_matters/june2008/06092008rett.htm
          Rett Syndrome is a
     neurodevelopmental disorder
Hypotonia – loss of muscle tone            Other Symptoms
                                           • autism like behaviors
Apraxia —inability to perform              • toe walking
  motor functions                          • sleep problems
•   loss of use hands                      • cognitive disabilities
•   repetitive hand movements              • seizures
•   diminished eye contact                 • breathing problems
                                           • teeth grinding
•   gait abnormalities
                                           • difficulty chewing
•   lack of speech development


            http://www.youtube.com/watch?v=rQvTgV7f2JM
        Rett syndrome is caused by
       mutations in the MECP2 gene




                                                            Bird, A. Biochem. Soc. Trans. (2008) 36, 575–583




http://ghr.nlm.nih.gov/dynamicImages/chromomap/mecp2.jpeg
    MECP2 GO Terms Suggest
           Function
Biological Process
• Negative regulation of transcription from RNA
  polymerase II promoter
Cellular Component
• Mitochondrion
• Nucleolus
• Nucleus *Also noted in Uniprot
Molecular Function
• DNA binding
• Double stranded methylated DNA binding
• Protein binding
• Transcription corepressor activity
  MECP2 Mouse GO Terms Shed More
    Light on Role in Rett Syndrome
Behavior                                    Transcription
adult locamotory behavior                   negative regulation of transcription,
response to hypoxia                         DNA dependent positive regulation of
social behavior                                transcription, DNA dependent
                                            regulation of transcription
Neurological
brain development                           Epigenetics
cerebellum development                      chromatin silencing
dendrite development                        genetic imprinting
long term synaptic potentiation             histone acetylation
negative regulation of neuron apoptosis     histone methylation
neurite development                         regulation of gene expression, epigenetic
neuromuscular process controlling posture   Other
neuron differentiation                      catecholamine secretion (hormone
neuron maturation                           controlling fight or flight response)
synaptic transmission                       respiratory gaseous exchange
synaptogenesis
The MECP2 gene encodes the
      MECP2 protein



                    SMART




                    Protein Data Bank
         MECP2 homologs are found
            in other mammals




Phylogeny.fr
      MECP2 domains are well
       conserved in homologs
Homo sapiens…………......
Pan troglodytes……………
Canis lupus familiaris …….
Bos taurus…………………
Rattus norvegicus…………
Mus musculus……………..
Danio rerio…………………
                             SMART
  The MECP2 protein represses
transcription of methylated genes




          http://www.germaco.net/intro_rett_gb.html
  MECP2 interacts with proteins that
form the histone deacetylase complex
   and other transcription factors
Pan troglodytes
                        Mus musculus


                      Sin3A



                  Danio rerio
  Gene Therapy Experiments
• Developed mouse model with silenced
  MECP2 that can be activated with injections of
  Tamoxifen
• Mice initially had Rett Syndrome phenotype
• After MECP2 was activated, symptoms
  disappeared
• Rett syndrome symptoms are not irreversible
• Not a direct therapeutic approach
          Future Directions
• Determine which genes are abnormally
  expressed in Rett Syndrome
  – Gel shift to determine which genes bind to
    MECP2. Use microarray to look at expression
    changes in these genes in the presence and
    absence of MECP2
  – Mass Spec analysis of brain tissue in MECP2 null
    mice vs. WT mice