Fig. 1
Pedigree and genetic analysis. A Pedigree of the family. There was no family history. The proband has an elder sister with normal appearance. The mother has no history of trauma or exposure to any known teratogens or intake of any medication during pregnancy. B Electropherograms of Sanger sequence. The heterozygous de novo variant in the patient, c.807C>A (GNAI3:NM_006496), is indicated by the red arrow (left panel). The same nucleotide in her parents is indicated by the blue arrow (middle and right panel). The amino acids translated from the DNA sequences are presented under each electropherogram. C Schematic diagram of Gαi3 (NP_006487.1). Five guanine nucleotide-binding site (G1–G5, black box) are located within GTP catalytic domains (yellow box). The catalytic domain is divided by an α helical domain (diagonal stripes). Consensus amino acid residues of the nucleotide-binding sites are boxed and indicated under each bonding site. Gαi3 variants from the literature are indicated in black and the novel variant identified in this case is indicated in red. D In silico three-dimensional views of the Gαi3. Wild-type Gαi3 was obtained from a database of annotated 3D structures generated by SWISS-MODEL (UniProtKB AC; P08754, PDB ID; 4g5o). Regions of the guanine nucleotide-binding site, G1–G4, are indicated in blue. The GDP-binding region concerning Asn269 is indicated by the red square (left panel). The side chain of Asn269 in wild-type Gαi3 makes a hydrogen bond to the N7 atom of the GDP (red broken line, middle panel). Lysin is a charged amino acid with a longer carbon skeleton compared to asparagine. The ε amino group of Lys269 is facing the opposite side (arrow), which would affect the hydrogen bond to GDP (right panel, GDP is not shown). The structure of the Gαi3 variant (p.Asn269Lys) was constructed based on the guanine nucleotide-binding protein G(k) subunit alpha by the SWISS-MODEL server homology modelling pipeline
