Intellectual disability (ID) occurs in 2-3% of newborns, resulting in lifetime of dependency on family and health care systems. ID has traditionally been viewed as untreatable. Recently, however, this view has been challenged with increasing evidence that the early postnatal period, during which the brain continues to develop, provides a potential therapeutic window.
We focus on disorders with ID caused by mutations in chromatin modifying enzymes. These chromatin modifiers regulate gene expression in the developing and maturing brain. The biochemical activity of chromatin modifiers is inherently reversible - for example, DNA can be methylated by DNA methyltransferases and subsequently demethylated through the action of TET enzymes - and we are investigating potential interventions to reverse the biochemical dysfunction that occurs in chromatin-based ID disorders.
We have generated a range of in vivo and in vitro models, including human neuroblastoma cell lines, carrying specific disease-associated variants and shown that these variants give rise to different molecular changes. By understanding the molecular consequences of specific variants, we shed light on aetiology of diseases with variable clinical presentations as well as the normal function of different domains of the chromatin proteins. Importantly, understanding that different variants in the same gene can cause different molecular effects highlights the fact that different treatment approaches for the same disorder may be needed for different classes of disease-associated variants.