Gαo-deficient mice (Gnao1−/−) have occasional seizures, severe impairment of motor-control, hyperalgesia, and behavioral abnormalities with early postnatal lethality.16,17 Although heterozygous Gnao1 knockout mice do not manifest seizures, a gain-of-function knock-in mutant murine model (Gnao1 Gly184Ser/+) has severe seizures with markedly increased frequency of interictal epileptiform discharges and sudden premature death. Animal model data thus suggest that pathogenic monoallelic GNAO1 mutations in humans may also result in a gain-of-function effect. Moreover, impaired protein localization and decreased GNAO1-mediated inhibition of calcium currents by norepinephrine compared to the wild type have been showed in in vitro functional expression systems.18 GNAO1 has also been implicated in the etiology of brain tumors, such as ependymoma and glioblastoma multiforme.19,20
