title: Novel variants in GNAI3 associated with auriculocondylar syndrome strengthen a common dominant negative effect.
abstract: Auriculocondylar syndrome is a rare craniofacial disorder comprising core features of micrognathia, condyle dysplasia and question mark ear. Causative variants have been identified in PLCB4, GNAI3 and EDN1, which are predicted to function within the EDN1-EDNRA pathway during early pharyngeal arch patterning. To date, two GNAI3 variants in three families have been reported. Here we report three novel GNAI3 variants, one segregating with affected members in a family previously linked to 1p21.1-q23.3 and two de novo variants in simplex cases. Two variants occur in known functional motifs, the G1 and G4 boxes, and the third variant is one amino acid outside of the G1 box. Structural modeling shows that all five altered GNAI3 residues identified to date cluster in a region involved in GDP/GTP binding. We hypothesize that all GNAI3 variants lead to dominant negative effects.
authors.affiliation: Centro de Pesquisas do Genoma Humano e Células Tronco, Departamento de Genetica e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Vanessa L
authors.initials: VL
authors.lastname: Romanelli Tavares
authors.affiliation: INSERM U1163, Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris, France.
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Gordon
authors.affiliation: Department of Clinical Genetics, Hospital of Rehabilitation of Craniofacial Anomalies, University of São Paulo (HRCA-USP), Bauru, Brazil.
authors.forename: Roseli M
authors.initials: RM
authors.lastname: Zechi-Ceide
authors.affiliation: Department of Clinical Genetics, Hospital of Rehabilitation of Craniofacial Anomalies, University of São Paulo (HRCA-USP), Bauru, Brazil.
authors.forename: Nancy Mizue
authors.initials: NM
authors.lastname: Kokitsu-Nakata
authors.affiliation: INSERM U1163, Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris, France.
authors.forename: Norine
authors.initials: N
authors.lastname: Voisin
authors.affiliation: Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Royal Children's Hospital, and Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Tiong Y
authors.initials: TY
authors.lastname: Tan
authors.affiliation: Department of Plastic and Maxillofacial Surgery, Royal Children's Hospital, Melbourne, Victoria, Australia.
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Heggie
authors.affiliation: Department of Clinical Genetics, Hospital of Rehabilitation of Craniofacial Anomalies, University of São Paulo (HRCA-USP), Bauru, Brazil.
authors.forename: Siulan
authors.initials: S
authors.lastname: Vendramini-Pittoli
authors.affiliation: Department of Otolaryngology - Head & Neck Surgery, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Evan J
authors.initials: EJ
authors.lastname: Propst
authors.affiliation: Department of Otolaryngology - Head & Neck Surgery, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Blake C
authors.initials: BC
authors.lastname: Papsin
authors.affiliation: Institute of Biosciences, University of São Paulo, São Paulo, Brazil.
authors.forename: Tatiana T
authors.initials: TT
authors.lastname: Torres
authors.affiliation: Leiden Genome Technology Center, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Henk
authors.initials: H
authors.lastname: Buermans
authors.affiliation: 1] Centro de Pesquisas do Genoma Humano e Células Tronco, Departamento de Genetica e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brazil [2] Instituto de Ciência e Tecnologia, Universidade Federal de São Paulo, São José dos Campos, Brazil.
authors.forename: Luciane Portas
authors.initials: LP
authors.lastname: Capelo
authors.affiliation: Leiden Genome Technology Center, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Johan T
authors.initials: JT
authors.lastname: den Dunnen
authors.affiliation: Department of Clinical Genetics, Hospital of Rehabilitation of Craniofacial Anomalies, University of São Paulo (HRCA-USP), Bauru, Brazil.
authors.forename: Maria L
authors.initials: ML
authors.lastname: Guion-Almeida
authors.affiliation: 1] INSERM U1163, Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris, France [2] Département de Génétique, Hôpital Necker-Enfants Malades AP-HP, Paris, France.
authors.forename: Stanislas
authors.initials: S
authors.lastname: Lyonnet
authors.affiliation: 1] INSERM U1163, Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris, France [2] Département de Génétique, Hôpital Necker-Enfants Malades AP-HP, Paris, France.
authors.forename: Jeanne
authors.initials: J
authors.lastname: Amiel
authors.affiliation: Centro de Pesquisas do Genoma Humano e Células Tronco, Departamento de Genetica e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Maria Rita
authors.initials: MR
authors.lastname: Passos-Bueno
mesh_terms: D001934:Branchial Region / Q000378:metabolism; D001938:Brazil; D004423:Ear / Q000002:abnormalities*; D004427:Ear Diseases / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000235:genetics*; D014644:Genetic Variation; D006801:Humans; D008297:Male; D010375:Pedigree; D010641:Phenotype; D011487:Protein Conformation
chemical_list: C498819:GNAI3 protein, human; D019206:GTP-Binding Protein alpha Subunits, Gi-Go