The Ontario Rett Syndrome Association (O.R.S.A.) Board of Directors has unanimously approved the funding of a $50,000 Research Grant to a joint grant application from Dr. Juan Ausio (Biochemistry and Microbiology, University of Victoria, BC) and Dr. John Vincent (Neurogenetics, University of Toronto).
Their application was one of several received and evaluated by O.R.S.A.’s Research Advisory Committee that comprised of prominent neurologists, geneticists and scientists from across Canada. It is entitled “Translational correlation of MeCP2 chromatin alterations in male and female missense mutations” and is a collaboration between two world-renowned investigators, with concise and achievable objectives.
The project revolves around the study of specific identified mutations in Rett syndrome (RTT) and aims to further the understanding of the pathogenesis of RTT and develop new insights into the factors affecting clinical phenotypes in RTT. DNA is the molecule responsible for the storage, retrieval and replication of the genetic material. In the nucleus of the cell, DNA interacts with proteins known as histones and the resulting association is called chromatin. In the brain, an additional highly abundant chromatin protein, MeCP2, is present that binds preferentially to methylated regions of DNA. Mutations of MeCP2 cause an impairment of the binding of this protein to DNA and hence to chromatin. Such alterations result in the Rett syndrome neurodevelopmental disease. Mutations of MeCP2 across the entire MeCP2 molecule are deleterious to different extents, all of them leading to Rett cases with different degrees of severity. However, neither the reason for this, nor the alterations of chromatin responsible, nor their relation to the extent of severity of the Rett syndrome outcomes are clearly understood. The idea behind this project is to combine the expertise of two well established groups in Canada working on MeCP2 and Rett syndrome to address such questions for two novel mutations of MeCP2:( Ala2Val) identified in three girls with classic Rett syndrome), and (Prol 52His) affecting the methyl binding domain (MBD)I, identified in an adult male with intellectual disability with additional comorbid features. This could potentially lead to further future studies aimed at discovering newer drug therapies.
The Hope Fund was established in 2014. This is the first grant being released from this fund and the largest grant released by O.R.S.A. to date. The funds for this research grant were raised through donations and fundraising activities. O.R.S.A. continues to support research excellence and the development of a wide scope of Rett syndrome research across Canada.
About Rett Syndrome
Rett syndrome is a neurodevelopmental condition characterized by the loss of spoken language and hand use, coupled with the development of distinctive hand stereotypies. This disorder is seen in infancy and occurs almost exclusively in females. It is usually caused by a mutation of the MECP2 gene on the X chromosome. Rett syndrome is found in all racial and ethnic groups throughout the world. It affects one in every ten thousand live female births. Early developmental milestones appear normal, but between 6-18 months of age, there is a delay or regression in development, particularly affecting speech, hand skills and gait. A hallmark of Rett syndrome is repetitive hand movements that may become almost constant while awake. Other more common medical issues encountered include epileptic seizures, muscle stiffness, osteoporosis and scoliosis. Despite its multiple handicaps, Rett syndrome is not a degenerative disease. Many individuals with Rett syndrome live long into adulthood. There is currently no cure.
About Ontario Rett Syndrome Association (O.R.S.A.)
The Ontario Rett Syndrome Association (O.R.S.A.) exists to ensure that children and adults with Rett syndrome are enabled to achieve their full potential and enjoy the highest quality of life within their communities.
Dr. Juan Ausio
Dr. Juan Ausió, Ph.D., is a Professor in the Department of Biochemistry and Microbiology, University of Victoria, BC, Canada. Dr. Juan Ausió’s research interests focus on structural characterization of biological macromolecular assemblies, and nuclear proteins with special emphasis on the chromosomal protein-DNA interactions. His current research include studies on histone-histone interactions, and histone/MeCP2-DNA interactions at the nucleosome level and at the higher order structure of chromatin in Rett’s syndrome and prostate cancer. Special attention is being paid to the influence of these interactions on biologically significant chemical modifications, both at the histone and at the DNA level (acetylation, phosphorylation, and methylation) and their epigenetic contribution.
Dr. John Vincent
Dr. John B. Vincent undertook his undergraduate studies in biochemistry at the University of Manchester. He completed his Ph.D. at University College London Medical School, London, in 1994, with Dr. Hugh Gurling, in the Department of Academic Psychiatry. Since then he has worked with Dr. James Kennedy in the Neurogenetics Section at the Clarke Division, Centre for Addiction and Mental Health (CAMH) in Toronto and with Dr. Stephen Scherer in the Dept. of Genetics at The Hospital for Sick Children, Toronto. Since 2002, he has worked as a Senior Scientist/Principal Investigator back at CAMH, and is a Professor in the Dept. of Psychiatry and cross-appointed in the Institute of Medical Science at the University of Toronto. His work is on the genetics of major psychiatric disorders, but with the main focus looking at the genetics and genomics of autism and intellectual disability, including Rett syndrome. In 2004, he co-authored a seminal paper on the identification of an alternative version of the Rett syndrome protein, MeCP2, with the implication that this new version is more relevant to Rett syndrome, which has since been shown by numerous studies to be correct (Mnatzakanian et al, 2004).