Role of CHAMP1, a neurodevelopmental disorder high risk gene, in human brain development and function

PROJECT SUMMARY Nonsense or missense mutations of the CHAMP1 gene, which encodes for a zinc-finger protein involved in the maintenance of kinetochore-microtubule attachment during mitosis and regulation of chromosomal segregation, causes a neurodevelopmental syndrome characterized by intellectual disability (ID), ASD-like behaviors,

microcephaly, hypotonia, and dysmorphic features. CHAMP1 interacts with POGZ, which encodes for a gene that causes the White-Sutton syndrome, and it is known that the interaction of these two proteins is lost in the presence of mutations. To date, 36 disease rare variants in CHAMP1 have been reported across studies

comprising nonsense, missense, and frameshift mutations. Recently, a Champ1+/- mouse model showed relatively mild learning and memory impairment and depression-like behaviors and delayed neuronal differentiation. Despite the mouse data, there is yet no study that focused on the human brain leaving the role of

CHAMP1 in human brain development totally unexplored. As such, our central hypothesis is that CHAMP1 loss of function alter neurogenesis and neuronal migration in human brain resulting in dysfunction of cortical local circuits. We propose a series of complementary approaches, including high-resolution imaging, single-cell multiomics,

and electrophysiology tools to explore CHAMP1 loss of function in the following specific aims: Specific Aim 1. Determine the influence of CHAMP1 loss of function in the development of forebrain cortical organoids. Specific Aim 2. Profile single cell level transcriptomic and epigenomic landscapes of CHAMP1 loss of function

organoids at different developmental stages. Specific Aim 3. Determine the effect of CHAMP1 loss of function in neuronal activity and local network.