De Novo Mutations in GNAO1, Encoding a Gαo Subunit of Heterotrimeric G Proteins, Cause Epileptic Encephalopathy

Abstract

Heterotrimeric G proteins, composed of α, β, and γ subunits, can transduce a variety of signals from seven-transmembrane-type receptors to intracellular effectors. By whole-exome sequencing and subsequent mutation screening, we identified de novo heterozygous mutations in GNAO1, which encodes a Gαo subunit of heterotrimeric G proteins, in four individuals with epileptic encephalopathy. Two of the affected individuals also showed involuntary movements. Somatic mosaicism (approximately 35% to 50% of cells, distributed across multiple cell types, harbored the mutation) was shown in one individual. By mapping the mutation onto three-dimensional models of the Gα subunit in three different complexed states, we found that the three mutants (c.521A>G [p.Asp174Gly], c.836T>A [p.Ile279Asn], and c.572_592del [p.Thr191_Phe197del]) are predicted to destabilize the Gα subunit fold. A fourth mutant (c.607G>A), in which the Gly203 residue located within the highly conserved switch II region is substituted to Arg, is predicted to impair GTP binding and/or activation of downstream effectors, although the p.Gly203Arg substitution might not interfere with Gα binding to G-protein-coupled receptors. Transient-expression experiments suggested that localization to the plasma membrane was variably impaired in the three putatively destabilized mutants. Electrophysiological analysis showed that Gαo-mediated inhibition of calcium currents by norepinephrine tended to be lower in three of the four Gαo mutants. These data suggest that aberrant Gαo signaling can cause multiple neurodevelopmental phenotypes, including epileptic encephalopathy and involuntary movements.

Phenotypic spectrum of GNAO1 variants: epileptic encephalopathy to involuntary movements with severe developmental delay

“…Patients with GNAO1 variants showed severe intellectual disability, motor developmental delay, and brain atrophy, further demonstrating that the aberration of Gα o affects normal brain development. In our previous report, 6 three of four patients showed OS, which is characterized by tonic spasms mainly in the neonatal period. 4 In this study, two patients showed migrating or multifocal complex partial seizures in their clinical course, similar to the findings of MPSI.…”

“…The c.607G4A is a recurrent variant, which was previously found in a patient showing childhood epilepsy and involuntary movement. 6 One variant (c.736G4A) specifically affects GNAO1 transcript variant 1, whereas the other three variants affect both transcript variants 1 and 2 (GenBank accession number NM_020988.2 and NM_138736.2, respectively). Web-based prediction tools suggested that these four variants could affect protein function (Supplementary Table 1).…”

“…5 We previously reported de novo GNAO1 variants in four patients with epileptic encephalopathy. 6 Three of them showed OS and one patient had childhood epilepsy. Interestingly, two of them showed involuntary movements, suggesting that GNAO1 variants can cause various neurological phenotypes with variable types of seizures.…”

Enhanced utility of family-centered diagnostic exome sequencing with inheritance model–based analysis: results from 500 unselected families with undiagnosed genetic conditions

“…21 In our first 500 unselected exome families, we detected mutations in this gene in four probands ( Table 4). Similar examples included recurrent 27 and we then identified another de novo mutation in this gene in another patient through retrospective data mining.…”

De Novo Mutations in YWHAG Cause Early-Onset Epilepsy

“…1 There are currently 51 established EE-associated genes, in which many causal mutations arise de novo. [2][3][4][5][6][7][8][9][10][11][12][13] However, with the advent of high-throughput sequencing, an increasing number of candidate genes are emerging with only a single reported de novo variant. 4,5 The interpretation of these findings remains challenging given that on average $0.5 de novo exonic mutations are expected per individual.…”