Koolen-de Vries-syndrome (KdVS), also known as 17q21.31 microdeletion syndrome, is caused by heterozygous loss of KANSL1. The main clinical features of this multisystemic disorder encompass a variety of symptoms like mild to moderate intellectual disability, developmental delay, epilepsy, and distinct facial features. Currently no therapy is available and only supportive care can be provided. Therefore, elucidating the pathophysiological mechanisms underlying the cognitive deficits is essential to aid the development of effective therapies.
KANSL1 is known to be a scaffold protein involved in the formation of the non-specific lethal (NSL) complex. This complex is regulating gene expression activation, mainly by acetylating histone 4 at lysine residue 16 (H4K16ac) making H4K16ac an interesting entry point to elucidate molecular mechanisms that are affected upon KANSL1 haploinsufficiency.
H4K16ac activates the expression of a broad set of genes including several autophagy-related genes (ATGs). Autophagy is a catabolic process important for the clearance of protein aggregates and damaged organelles within the cell, which is essential for cell homeostasis and survival. In neurons autophagy showed to be essential, not only for cell homeostasis, but also for regulation of development and function. Disruption in autophagy therefore can lead to impairments in neuronal development and synaptic transmission and might play an essential role in the pathophysiology of KdVS.
In our studies, we made use of recent advances in induced pluripotent stem cell (iPSC) technology and developed a human in vitro model for KdVS. Patient as well as control derived iPSCs are differentiated into a homogeneous population of cortical excitatory neurons by means of forced over expression of the transcription factor Neurogenin 2. Neuronal and synaptic maturation can be monitored using imaging modalities, molecular biology techniques, as well as single cell and neuronal network electrophysiological recordings. This way the model allows us to get detailed insights into disease progression within the context of a patient specific, genetic background aiming to link deregulated autophagy to a neuronal functional phenotype. More specifically, it was found that changes in gene expression resulted in hyperactivated autophagy in KdVS patient derived iPSCs. Next to increased autophagy, in neurons derived from these iPSCs, we observed a reduced number of synapses and aberrant neuronal network formation. In a next step we now try to use different drugs to reduce activation of the autophagy pathway and thereby restore synaptic function and neuronal network formation.