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De Novo mutations in GNAO1, encoding a G?o subunit of heterotrimeric G proteins, cause epileptic encephalopathy.

ABSTRACT: Heterotrimeric G proteins, composed of ?, ?, and ? 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 G?o 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 G? 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 G? 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 G? 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 G?o-mediated inhibition of calcium currents by norepinephrine tended to be lower in three of the four G?o mutants. These data suggest that aberrant G?o signaling can cause multiple neurodevelopmental phenotypes, including epileptic encephalopathy and involuntary movements.

SUBMITTER: Nakamura K

PROVIDER: S-EPMC3769919 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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De Novo mutations in GNAO1, encoding a Gαo subunit of heterotrimeric G proteins, cause epileptic encephalopathy.

Nakamura Kazuyuki K Kodera Hirofumi H Akita Tenpei T Shiina Masaaki M Kato Mitsuhiro M Hoshino Hideki H Terashima Hiroshi H Osaka Hitoshi H Nakamura Shinichi S Tohyama Jun J Kumada Tatsuro T Furukawa Tomonori T Iwata Satomi S Shiihara Takashi T Kubota Masaya M Miyatake Satoko S Koshimizu Eriko E Nishiyama Kiyomi K Nakashima Mitsuko M Tsurusaki Yoshinori Y Miyake Noriko N Hayasaka Kiyoshi K Ogata Kazuhiro K Fukuda Atsuo A Matsumoto Naomichi N Saitsu Hirotomo H

American journal of human genetics 20130829 3

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% ...[more]

PMID: 23993195

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Project description:The solute carrier (SLC) superfamily encompasses >400 transmembrane transporters involved in the exchange of amino acids, nutrients, ions, metals, neurotransmitters and metabolites across biological membranes. SLCs are highly expressed in the mammalian brain; defects in nearly 100 unique SLC-encoding genes (OMIM: https://www.omim.org) are associated with rare Mendelian disorders including developmental and epileptic encephalopathy and severe neurodevelopmental disorders. Exome sequencing and family-based rare variant analyses on a cohort with neurodevelopmental disorders identified two siblings with developmental and epileptic encephalopathy and a shared deleterious homozygous splicing variant in SLC38A3. The gene encodes SNAT3, a sodium-coupled neutral amino acid transporter and a principal transporter of the amino acids asparagine, histidine, and glutamine, the latter being the precursor for the neurotransmitters GABA and glutamate. Additional subjects with a similar developmental and epileptic encephalopathy phenotype and biallelic predicted-damaging SLC38A3 variants were ascertained through GeneMatcher and collaborations with research and clinical molecular diagnostic laboratories. Untargeted metabolomic analysis was performed to identify novel metabolic biomarkers. Ten individuals from seven unrelated families from six different countries with deleterious biallelic variants in SLC38A3 were identified. Global developmental delay, intellectual disability, hypotonia, and absent speech were common features while microcephaly, epilepsy, and visual impairment were present in the majority. Epilepsy was drug-resistant in half. Metabolomic analysis revealed perturbations of glutamate, histidine, and nitrogen metabolism in plasma, urine, and CSF of selected subjects, potentially representing biomarkers of disease. Our data support the contention that SLC38A3 is a novel disease gene for developmental and epileptic encephalopathy and illuminate the likely pathophysiology of the disease as perturbations in glutamine homeostasis.

Dataset Information

De Novo mutations in GNAO1, encoding a G?o subunit of heterotrimeric G proteins, cause epileptic encephalopathy.

Publications

De Novo mutations in GNAO1, encoding a Gαo subunit of heterotrimeric G proteins, cause epileptic encephalopathy.

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