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Molecular basis of a novel oncogenic mutation in GNAO1.

ABSTRACT: Heterotrimeric G proteins are molecular switches that control signal transduction, and their dysregulation can promote oncogenesis. Somatic mutations in GNAS, GNAI2 and GNAQ genes induce oncogenesis by rendering G? subunits constitutively activated. Recently the first somatic mutation, arginine(243) ? histidine (R243H) in the GNAO1 (G?o) gene was identified in breast carcinomas and shown to promote oncogenic transformation when introduced into cells. Here, we provide the molecular basis for the oncogenic properties of the G?o R243H mutant. Using limited proteolysis assays, nucleotide-binding assays, and single-turnover and steady-state GTPase assays, we demonstrate that the oncogenic R234H mutation renders G?o constitutively active by accelerating the rate of nucleotide exchange; however, this mutation does not affect G?o's ability to become deactivated by GTPase-activating proteins (GAPs) or by its intrinsic GTPase activity. This mechanism differs from that of previously reported oncogenic mutations that impair GTPase activity and GAP sensitivity without affecting nucleotide exchange. The constitutively active G?o R243H mutant also enhances Src-STAT3 signaling in NIH-3T3 cells, a pathway previously shown to be directly triggered by active G?o proteins to promote cellular transformation. Based on structural analyses, we propose that the enhanced rate of nucleotide exchange in G?o R243H results from loss of the highly conserved electrostatic interaction of R243 with E43, located in the in the P-loop that represents the binding site for the ?- and ?-phosphates of the nucleotide. We conclude that the novel R234H mutation imparts oncogenic properties to G?o by accelerating nucleotide exchange and rendering it constitutively active, thereby enhancing signaling pathways, for example, src-STAT3, responsible for neoplastic transformation.

SUBMITTER: Garcia-Marcos M

PROVIDER: S-EPMC3349449 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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Molecular basis of a novel oncogenic mutation in GNAO1.

Garcia-Marcos M M Ghosh P P Farquhar M G MG

Oncogene 20110214 23

Heterotrimeric G proteins are molecular switches that control signal transduction, and their dysregulation can promote oncogenesis. Somatic mutations in GNAS, GNAI2 and GNAQ genes induce oncogenesis by rendering Gα subunits constitutively activated. Recently the first somatic mutation, arginine(243) → histidine (R243H) in the GNAO1 (Gαo) gene was identified in breast carcinomas and shown to promote oncogenic transformation when introduced into cells. Here, we provide the molecular basis for the ...[more]

PMID: 21317923

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Project description:Background GNAO1 variants have been found to be associated with epileptic encephalopathies, developmental delays (DDs), and movement disorders (MDs). Therapies for patients with GNAO1 variants vary. However, treatments for GNAO1-related diseases are still in their infancy. Previous reports suggest that few pharmacological treatments are effective for patients with GNAO1 variant-related MDs. Deep brain stimulation (DBS) treatment appears to be effective, however surgical procedures and equipment failures pose risks to the patients. Effectiveness for oxcarbazepine (OXC) in GNAO1 variant-related MDs is first reported in our study, and it expand the effective drugs for MD treatment. Case Description We report the case of a 5-year-old male patient with a MD, who suffered from hypotonia and refractory choreoathetosis. The patient was found to have a DD and an intellectual disability. A de-novo variant of the GNAO1 gene (NM_138736: exom6: c.709G>A [p. Glu237Lys]) was identified by whole exome sequencing (WES) when he was 8 months old. The patient visited our hospital at the age of 4 years and 3 months because of fever and recurrent convulsions. Electroencephalogram (EEG) results show abnormal spikes, and magnetic resonance imaging (MRI) showed the enlargement of the lateral ventricles. The administration of tiapride hydrochloride, phenobarbital, midazolam, and hormones had no effect. OXC treatment was then initiated. No MD behaviors, such as rigidity and twisting of the limbs and trunk, or chorea, were observed after 10 days OXC treatment. Eventually, incremental doses of OXC were effective, and our patient achieved good control of his MD. Conclusions We are the first to demonstrate the role of OXC in alleviating MDs associated with GNAO1 mutations. This report provides a novel possibility for the clinical treatment of this rare disease. To manage MDs associated with GNAO1 mutations, we recommend that OXC treatment be attempted before invasive surgical therapy.

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Molecular basis of a novel oncogenic mutation in GNAO1.

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Molecular basis of a novel oncogenic mutation in GNAO1.

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