Research Awards
Bryan M. Turner, Ph.D.
University of Birmingham Medical School
"Histone Deacetylase Complexes Assembled on Wild-Type and Mutant MeCP2: Functional Properties and Genomic Distribution"
1-Year Award: $49,940
Final Report (November 2003)
The DNA-binding protein MeCP2 has a role in controlling the expression of many different genes. It is believed that the mutations in MeCP2 that cause Rett Syndrome, exert their effects by altering patterns of gene expression and thereby disrupting normal pathways of brain development. Mutations in MeCP2 are commonly found in either the region of the protein that binds to DNA, or in a region (called the TRD) that is believed to associate with other specific proteins to assemble a multi-protein gene regulatory complex. In our project we used molecular genetic techniques to make MeCP2 proteins that had mutations the same as those found in Rett patients. We were able to demonstrate that MeCP2 with mutations in the protein-binding domain can assemble a gene regulatory complex with the same constituents as that assembled by normal MeCP2, but does so less efficiently. We used microscopical analyses to show that these mutant complexes are targeted to the same DNA regions as normal MeCP2 complexes. In contrast, MeCP2 mutated in the DNA-binding domain, was not properly targeted. Our results suggest that mutations in the protein-binding region of MeCP2 may lead to the symptoms of Rett syndrome by rather subtle, quantitative effects.
Bryan M. Turner, Ph.D.University of Birmingham Medical School
"Histone Deacetylase Complexes Assembled on Wild-Type and Mutant MeCP2: Functional Properties and Genomic Distribution"
1-Year Award: $49,940
Final Report (November 2003)
The DNA-binding protein MeCP2 has a role in controlling the expression of many different genes. It is believed that the mutations in MeCP2 that cause Rett Syndrome, exert their effects by altering patterns of gene expression and thereby disrupting normal pathways of brain development. Mutations in MeCP2 are commonly found in either the region of the protein that binds to DNA, or in a region (called the TRD) that is believed to associate with other specific proteins to assemble a multi-protein gene regulatory complex. In our project we used molecular genetic techniques to make MeCP2 proteins that had mutations the same as those found in Rett patients. We were able to demonstrate that MeCP2 with mutations in the protein-binding domain can assemble a gene regulatory complex with the same constituents as that assembled by normal MeCP2, but does so less efficiently. We used microscopical analyses to show that these mutant complexes are targeted to the same DNA regions as normal MeCP2 complexes. In contrast, MeCP2 mutated in the DNA-binding domain, was not properly targeted. Our results suggest that mutations in the protein-binding region of MeCP2 may lead to the symptoms of Rett syndrome by rather subtle, quantitative effects.