Adrian Bird

Adrian Bird, Buchanan Professor of Genetics at the University of Edinburgh.

Rett Syndrome – a rare and debilitating autism spectrum disorder that affects the development of the brain – is caused by changes in the DNA in the MECP2 gene. Our work with the Patrick Wild Centre uses biochemistry, cell biology and genetics to study the molecular basis of this condition to better understand its origin and the potential of reversal 

RETT SYNDROME – CAN IT BE REVERSED
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Rett syndrome is caused by mutations in the gene that encodes the MeCP2 protein. The image shows a model for how the MeCP2 protein may act as a bridge between methylated sites on DNA and a large multiprotein machine that represses gene expression (NCoR/SMRT). Loss of this bridging function either by mutation of the DNA binding surface or NCoR/SMRT binding surface of MeCP2 (see crosses) results in Rett syndrome. Nucleosomes and their N-terminal tails are in grey, DNA is black and methyl-CpG sites are red circles. The blue triangles represent acetylated lysines (Ac) on histone tails, which can be removed by NCoR/SMRT. X marks the sites two common Rett mutations that change threonine 158 to methionine (T158M) and arginine 306 to cysteine (R306C).

The MECP2 gene contains instructions to make a protein — called MeCP2 — that is vital for brain development. Our laboratory discovered this vital protein and we also found that MeCP2 reads an epigenetic signal on chromosomes known as DNA methylation. MeCP2 appears to form bridge between methylated sites on chromosomes and a large protein complex that silences genes.

Our work seeks to define the binding pattern of MeCP2 on chromosomes at high resolution and to test theories regarding its role in the regulation of gene expression. In addition to identifying MeCP2, my team created the first animal model of Rett syndrome and we also showed that the model could accurately mimic the human condition. Perhaps more remarkable still, our work revealed that the Rett-like condition in mice was fully reversible if the MECP2 gene was activated after the animals become symptomatic.

The finding suggests that contrary to expectation, Rett syndrome is a curable disorder in humans. These discoveries have triggered a worldwide effort to find a cure for Rett syndrome. Now, our work is focussed on creating further models corresponding to specific Rett mutations so that we can understand their specific molecular contributions to the disease. Interestingly, MeCP2 is also implicated in X-linked mental retardation and other intellectual disabilities characterised by developmental delay. In addition, over-expression of MeCP2 due to duplication of the gene gives rise to a distinct autism spectrum disorder.

Understanding how the protein contributes to brain function is therefore a priority. We are also looking to uncover potential new drugs by studying pharmacological agents that could affect how MeCP2 works. Inhibitors or stabilisers of either normal or mutant MeCP2 function may reveal small molecules with the potential to treat MeCP2-related disorders, including over-expression. Alternatively, the prospect of gene therapy, ideally through genome editing, is of widespread interest for treatment of a variety of genetic disorders, including intellectual disability.

We are interested in developing technologies that may one day facilitate this therapeutic approach.

Email: A.Bird@ed.ac.uk

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