Role of Heterotrimeric G Proteins in Cilia Assembly and Pathogenesis of Neurodevelopmental Disorders

Key Words: Heterotrimeric G proteins, GNAI1, Cilia, C. elegans, CRISPR, Neurodevelopmental disorders

Neurodevelopmental disorders (NDDs) in children comprise a range of conditions that include autism spectrum disorders, developmental delay, intellectual disability, and attention-deficit/hyperactivity disorder (ADHD). Our project is focused on the gene called GNAI1. Mutations in this gene cause a severe NDD associated with developmental delay, seizures, and autistic features. At this time, it remains unknown why or how GNAI1 mutations disrupt normal neurodevelopmental processes resulting in disease. Therefore, there is an urgent need to define the role of GNAI1 in development of the nervous system and determine how patient mutations interfere with this gene’s normal cellular functions leading to NDD. Without this knowledge, discovery of therapeutic interventions to improve NDD patients’ quality of life would be hindered.

We have discovered that the GNAI1 gene is critical for building primary cilia – sensory structures that are present on the surface of all nerve cells and that function akin to cellular antennae detecting and transmitting signals from cells’ environment. The proper function of these structures is absolutely essential for normal development of the nervous system, and when disrupted, leads to genetic disorders with neurodevelopmental features. Using cutting-edge genome engineering and microscopy tools in a genetically tractable experimental model, we seek to determine how GNAI1 regulates assembly of primary cilia and to build a genetic pipeline for rapid functional classification of a growing number of GNAI1 variants from NDD patients. This work is relevant to child health because it will foster a better understanding of the GNAI1 NDD etiology and facilitate the search for effective therapeutic targets to manage NDD symptoms and thereby improve well-being of individuals living with these conditions.