Rett Syndrome (RTT) is a severe neurological disorder diagnosed almost exclusively in girls. Children with RTT appear to develop normally until 6 to 18 months of age, when they enter a period of regression, losing speech and motor skills. Most develop repetitive hand movements, irregular breathing patterns, seizures and extreme motor control problems. RTT leaves its victims profoundly disabled, requiring maximum assistance with every aspect of daily living. There is no cure.
RTT is caused by mutations in a gene (MECP2) that regulates expression of other genes. Genes are made up of long stretches of nucleotide bases that are divided into exons (sequences that code for protein) and introns (non-coding sequences). Genes make proteins in a multi-step process. The first, called transcription, takes place in the cell nucleus where DNA is copied into RNA. The second step involves cutting out the introns and pasting together the exons to make up the mature RNA. This RNA is then translated into proteins.
There is a wealth of data to suggest that MECP2 is a transcriptional repressor, meaning it turns off or down-regulates the production of other proteins by shutting down transcription. To date, a handful of MECP2 target genes have been identified.
The paradigm of one gene to one protein has recently given way to the realization that genes encode multiple proteins through a process called alternative splicing, whereby different combinations of exons are pasted together. Furthermore, genes can also have multiple functions. This phenomenon helps to explain why humans are so much more complex than worms or fruit flies, despite having similar numbers of genes.
Zoghbi and colleagues discovered that the MeCP2 protein is multifunctional. Beyond its role as a transcriptional repressor it also acts as a splicing regulator. In support of this finding Zoghbi and colleagues observed alternative splicing abnormalities in the mutant mouse model for RTT.
"The finding that MeCP2 functions in two steps of RNA processing, regulation of RNA levels and regulation of the variant molecules that can be generated from these RNAs is quite exciting. RNA splicing occurs extensively in the nervous system and is critical for many key neuronal functions. MeCP2's role in this process might provide insight about RNA molecules whose altered splicing contributes to the diverse features of RTT and related disorders," stated Huda Zoghbi. "Once we discover the RNA changes responsible for various features of RTT, we can begin to explore pharmacologic targets to alleviate the symptoms of the disease."
"There was never a doubt that RTT is a complex disease. However, we now propose that its molecular etiology is also complex: MECP2, the gene mutated in RTT, encodes a protein involved in controlling not only the quantity, but also the quality of the protein repertoire of the cell. Thus, we believe that our findings should modify the framework for the identification of key players in RTT pathogenesis by adding mis-spliced genes to the challenge," said Juan Young, first author of the paper.
Since its inception in late 1999, RSRF has become the largest private source of funds for RTT research in the world. "Mutations in the MECP2 gene can lead not only to RTT but also to autism and a variety of other mental disorders. This newly discovered role of MECP2 might therefore hold broad implications for understanding these devastating disorders and point to much needed treatments," stated Monica Coenraads, co-founder and Director of Research for RSRF.
For more information on RTT or the Foundation please visit our website at www.rsrf.org
Journal
Proceedings of the National Academy of Sciences