Decoding GNAO1 Mutations Using Caenorhabditis elegans Model System: Past Approaches and Future Prospectives

GNAO1 encephalopathies are a group of neglected genetic disorders primarily occurring due to de-novo point mutations in the Gαo protein-encoding gene in human GNAO1. This gene is reported to be highly conserved among Caenorhabditis elegans (C. elegans) and humans, with a sequence similarity of nearly 80%. Signaling pathways involved in various neurotransmitters, including GPCR pathways can be easily studied in the C. elegans model system. Therefore, using this model system to delineate downstream effectors and clinical targets to Gαo can be highly advantageous. Mutations that cause GNAO1 encephalopathy can be easily replicated in transgenic C. elegans and validated by rescuing phenotypic defects, primarily locomotion and egg-laying defects in worms. Although there are recent technical advancements in understanding the interacting proteins, there are unclear and uncertain hypotheses that explain the effect of Gαo mutations in humans. Coming to the clinical aspect of this disorder, there are no available approved diagnostic procedures to detect GNAO1 encephalopathy in the early stages of life. The present diagnostic procedures reiterate symptoms and overlap with other neurological symptoms that record neglected data of cases. Therefore, here we provide an overview of past research and a perspective of future work, with the primary objective of focusing on GNAO1 encephalopathy.