Abstracts

Rationale: G-proteins represent a diverse and ubiquitous set of effectors of metabotropic receptors integral to the proper functioning of the central nervous system. Each G-protein is a heterotrimer composed of alpha, beta, and gamma subunits. There are 12 gamma (γ) subunit subtypes, each contributing an element of specificity to the signaling pathway, effectuating GTPase activity and G protein-effector interactions (Schwindinger, 2012; Khan, 2013). The gamma 3 subunit (γ3) transcript, encoded by GNG3 gene on chromosome 11q12.3, is predominantly expressed in the brain, with increasing levels expressed during postnatal development (Asano, 1995, Kelly 2008). In in vivo studies, homozygous GNG3 knockout mice exhibited increased susceptibility to seizures, as well as reduced lifespan attributed to seizure-induced death (Schwindinger, 2004). These results strongly suggest a critical role for γ3 in the regulation of neuronal excitability and signaling pathway mediating seizure susceptibility. We describe a single family of Iraqi descent, in which three siblings of consanguineous, healthy parents share homozygous GNG3 mutations conferring a clinical spectrum of profound global developmental delays, hypotonia, cortical visual impairment, infantile spasms, and severe infantile-onset epileptic encephalopathy. The parents are first cousins, and family history is further significant for two maternal first cousins once removed with similarly severe developmental delay and epilepsy, a third, more distant maternal relative with severe epilepsy and delays, and two paternal first cousins with epilepsy and varying degrees of cognitive delays. This will be the first reported case of homozygous GNG3 mutations in human patients. Methods: IRB-approved family studies on over thirty additional individuals are underway, with the intent of tracking these variants throughout this consanguineous family and determining whether the similarly affected cousins have the same genetic diagnosis as our patients. Testing kits and consent forms have been sent to thirty-eight family members, including five additional affected individuals. Sanger sequencing will be performed on DNA from all individuals who return kits in order to check for the GNG3 variant found in our three probands.  Results: Family studies have not yet been completed, however we anticipate that this will be done by September of this year at the latest. Conclusions: We plan to utilize family studies to demonstrate that the GNG3 mutations present in this family are causative for the epilepsy and neurodevelopmental concerns seen in the eight similarly affected individuals. If our hypothesis is correct, we will be able to provide substantial evidence for GNG3 as a cause of epilepsy and cognitive impairment in humans.  Funding: Institutional support from UC Denver