Grant: Project Grant

Proteins are fundamental building blocks within all cells of our bodies, and many diseases are related to improper functioning of proteins. After they are made in the cells, many proteins need to be further modified to be fully functional. These modifications are important for regulating protein functions. One newly discovered protein modification is acetylation of specific lysine residues on proteins. Acetylation means addition of a chemical group called 'acetyl', whereas the term 'lysine residue' refers to something that is similar to the amino acid lysine. This modification, known as lysine acetylation, occurs in diverse organisms from bacteria to humans. Problems with lysine acetylation can cause genetic diseases, cancer and other pathological conditions. A protein called KAT6A plays a role in regulating lysine acetylation in humans. Its gene is mutated in patients with a developmental disorder characterized by intellectual disability and developmental delay. We have found that KAT6A and its related protein, KAT6B, are intimately associated with a third protein known as BRPF1. Moreover, we have recently demonstrated that the BRPF1 gene is mutated in patients with a novel developmental disorder showing intellectual disability. Importantly, our research has led to two new genetic diseases being named: Intellectual Developmental Disorder with Dysmorphic Facies and Ptosis, and Li-Ghorbani-Weisz-Hubshman syndrome. In the current research project, we will determine the biological functions of KAT6A, KAT6B and BRPF1 in the brain. By using stem cell and mouse models, we will investigate whether and how patient-derived KAT6A, KAT6B and BRPF1 mutations cause intellectual disability. The results will help us develop diagnostic tools, preventive measures and therapeutic interventions for these and related diseases. The results will shed new light on the development of human brain and intelligence, thus helping us understand different types of behaviours (good or bad).