Huije 'Jade' Feng, MSU Pharmacology & Toxicology,

  • Jan 25, 2017
Topic: “Genotype-phenotype Correlation of GNAO1 Mutations in Epileptic Encephalopathy”
Date: Wednesday, January 25, 2017
Time: 1p-2p
Place: B448 Life Science Bldg 
 

 

Epilepsy associated genes provide critical insights into the mechanisms of epilepsy genesisand are revolutionizing our understanding in the development of clinical intervention inepilepsy. The most well studied genes encode ion channels, but it remains a challenge to convert this knowledge into therapeutic strategies. G protein-coupled receptors (GPCRs) and their downstream effectors, a major group of drug targets, were supported as epilepsy-related by a 2013 report with four de novo mutations in GNAO1. GNAO1 encodes the heterotrimeric G protein Gαo, the most abundant G protein in the mammalian brain, which couples to many GPCRs to regulate neurotransmitter release and neural development. Nineteen GNAO1 mutations have been reported since 2013, yet their role in the development of epilepsy remains unclear. Patients carrying GNAO1 mutations show a broad spectrum of symptoms including developmental delay, recurrent epileptic seizures, and movement disorder. Therefore it is crucial to correlate GNAO1 mutations, which result in different functional ramifications, to different onset of symptoms (Aim 1). Independently, we have reported a heterozygous mutant mouse with a knock-in Gnao1 mutation G184S displaying perinatal lethality, rare seizures and sudden death. This mutation renders Gαo  insensitive to inhibition by regulator of G protein-signaling (RGS) protein, resulting in a gain-of-function Gαo. Neural circuitry studies (Aim 2) and behavior studies (Aim 3) of motor dysfunction on this mouse model will aid in the selection for treatment options in patients with GNAO1 mutations. In this project, I will characterize the genotype-phenotype link between in vitro studies and human patients. Furthermore, I will evaluate whether the mouse model mentioned above is a sufficient model to study GNAO1 associated epileptic encephalopathy