title: 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.
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, Japan.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Nakamura
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Kodera
authors.forename: Tenpei
authors.initials: T
authors.lastname: Akita
authors.forename: Masaaki
authors.initials: M
authors.lastname: Shiina
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Kato
authors.forename: Hideki
authors.initials: H
authors.lastname: Hoshino
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Terashima
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Osaka
authors.forename: Shinichi
authors.initials: S
authors.lastname: Nakamura
authors.forename: Jun
authors.initials: J
authors.lastname: Tohyama
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Kumada
authors.forename: Tomonori
authors.initials: T
authors.lastname: Furukawa
authors.forename: Satomi
authors.initials: S
authors.lastname: Iwata
authors.forename: Takashi
authors.initials: T
authors.lastname: Shiihara
authors.forename: Masaya
authors.initials: M
authors.lastname: Kubota
authors.forename: Satoko
authors.initials: S
authors.lastname: Miyatake
authors.forename: Eriko
authors.initials: E
authors.lastname: Koshimizu
authors.forename: Kiyomi
authors.initials: K
authors.lastname: Nishiyama
authors.forename: Mitsuko
authors.initials: M
authors.lastname: Nakashima
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Tsurusaki
authors.forename: Noriko
authors.initials: N
authors.lastname: Miyake
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Hayasaka
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Ogata
authors.forename: Atsuo
authors.initials: A
authors.lastname: Fukuda
authors.forename: Naomichi
authors.initials: N
authors.lastname: Matsumoto
authors.forename: Hirotomo
authors.initials: H
authors.lastname: Saitsu
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D004569:Electroencephalography; D004827:Epilepsy / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D059472:Exome / Q000235:genetics; D005260:Female; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000737:chemistry / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D021381:Protein Transport; D017422:Sequence Analysis, DNA; D015398:Signal Transduction / Q000235:genetics
chemical_list: C584143:GNAO1 protein, human; D050505:Mutant Proteins; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D002118:Calcium