Bromodomain and PHD finger containing protein 1 (BRPF1) is a multivalent chromatin reader that acts as a scaffold for histone acetyltransferases KAT6A and KAT6B. The BRPF1 complex plays essential roles in neurodevelopment, with BRPF1 loss leading to neurodevelopmental disorders (NDDs). Intellectual Developmental Disorder with Dysmorphic Facies and Ptosis (IDDDFP) is caused by BRPF1 haploinsufficiency. Another BRPF1-associated NDD is 3p25.3 microdeletion syndrome, caused by a variable deletion in the 3p25.3 region that often encompasses BRPF1. Both disorders are characterised by intellectual disability and global developmental delay. Given that acetylation is a reversible process, patients with neurodevelopmental disorders associated with acetylation defects may potentially be treated postnatally by supplementing with compounds to promote acetylation, such as acetyl donors or histone deacetylases (HDAC) inhibitors.
Thus far, we have made mouse models for each of these disorders to investigate the phenotype and underlying molecular deficits. Our novel mouse model of 3p25.3 microdeletion syndrome has perinatal lethality owing to a ventricular septal defect (VSD), which is also seen in human patients. We have begun trialling treatments for both disorders using E14.5 NSC’s, and furthermore we can translate this in vivo to Brpf1+/- mice as they survive to adulthood.