The role of methyl cpg binding protein 2 in rett syndrome
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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. Hypotonia – loss of muscle tone Apraxia —inability to perform motor functions loss of use hands repetitive hand movements diminished eye contact

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The role of methyl cpg binding protein 2 in rett syndrome

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

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

Rett Syndrome is a neurodevelopmental disorder

http://www.youtube.com/watch?v=rQvTgV7f2JM


Rett syndrome is caused by mutations in the mecp2 gene
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
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

adult locamotory behavior

response to hypoxia

social behavior

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

Transcription

negative regulation of transcription,

DNA dependent positive regulation of transcription, DNA dependent

regulation of transcription

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

MECP2 Mouse GO Terms Shed More Light on Role in Rett Syndrome



Mecp2 homologs are found in other mammals
MECP2 homologs are found in other mammals

Phylogeny.fr


Mecp2 domains are well conserved in homologs
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
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 deacetylase complex and other transcription factors

Mus musculus

Sin3A

Danio rerio


Gene therapy experiments
Gene Therapy Experiments deacetylase complex and other transcription factors

  • 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
Future Directions deacetylase complex and other transcription factors

  • 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


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