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
Apraxia —inability to perform
motor functions
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loss of use hands
repetitive hand movements
diminished eye contact
gait abnormalities
lack of speech development
Other Symptoms
• autism like behaviors
• toe walking
• sleep problems
• cognitive disabilities
• seizures
• breathing problems
• teeth grinding
• difficulty chewing
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
response to hypoxia
social behavior
negative regulation of transcription,
DNA dependent positive regulation of
transcription, DNA dependent
regulation of transcription
Neurological
brain development
cerebellum development
dendrite development
long term synaptic potentiation
negative regulation of neuron apoptosis
neurite development
neuromuscular process controlling posture
neuron differentiation
neuron maturation
synaptic transmission
synaptogenesis
Epigenetics
chromatin silencing
genetic imprinting
histone acetylation
histone methylation
regulation of gene expression, epigenetic
Other
catecholamine secretion (hormone
controlling fight or flight response)
respiratory gaseous exchange
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