title: Novel GNB1 mutations disrupt assembly and function of G protein heterotrimers and cause global developmental delay in humans.
abstract: Global developmental delay (GDD), often accompanied by intellectual disability, seizures and other features is a severe, clinically and genetically highly heterogeneous childhood-onset disorder. In cases where genetic causes have been identified, de novo mutations in neuronally expressed genes are a common scenario. These mutations can be best identified by exome sequencing of parent-offspring trios. De novo mutations in the guanine nucleotide-binding protein, beta 1 (GNB1) gene, encoding the Gβ1 subunit of heterotrimeric G proteins, have recently been identified as a novel genetic cause of GDD. Using exome sequencing, we identified 14 different novel variants (2 splice site, 2 frameshift and 10 missense changes) in GNB1 in 16 pediatric patients. One mutation (R96L) was recurrently found in three ethnically diverse families with an autosomal dominant mode of inheritance. Ten variants occurred de novo in the patients. Missense changes were functionally tested for their pathogenicity by assaying the impact on complex formation with Gγ and resultant mutant Gβγ with Gα. Signaling properties of G protein complexes carrying mutant Gβ1 subunits were further analyzed by their ability to couple to dopamine D1R receptors by real-time bioluminescence resonance energy transfer (BRET) assays. These studies revealed altered functionality of the missense mutations R52G, G64V, A92T, P94S, P96L, A106T and D118G but not for L30F, H91R and K337Q. In conclusion, we demonstrate a pathogenic role of de novo and autosomal dominant mutations in GNB1 as a cause of GDD and provide insights how perturbation in heterotrimeric G protein function contributes to the disease.
authors.affiliation: Institute of Neurogenetics, University of Lübeck, 23538?Lübeck, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Lohmann
authors.affiliation: Department of Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Ikuo
authors.initials: I
authors.lastname: Masuho
authors.affiliation: Department of Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Dipak N
authors.initials: DN
authors.lastname: Patil
authors.affiliation: Institute of Neurogenetics, University of Lübeck, 23538?Lübeck, Germany.
authors.forename: Hauke
authors.initials: H
authors.lastname: Baumann
authors.affiliation: Institute of Neurogenetics, University of Lübeck, 23538?Lübeck, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Hebert
authors.affiliation: Institute of Neurogenetics, University of Lübeck, 23538?Lübeck, Germany.
authors.forename: Sofia
authors.initials: S
authors.lastname: Steinrücke
authors.affiliation: Centogene AG, 18057 Rostock, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Trujillano
authors.affiliation: Department of Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Nickolas K
authors.initials: NK
authors.lastname: Skamangas
authors.affiliation: Neurology Clinic, University of Belgrade, 11000 Belgrade, Serbia.
authors.forename: Valerija
authors.initials: V
authors.lastname: Dobricic
authors.affiliation: Institut fur Humangenetik, Universität zu Lübeck, 23538 Lübeck, Germany.
authors.forename: Irina
authors.initials: I
authors.lastname: Hüning
authors.affiliation: Institut fur Humangenetik, Universität zu Lübeck, 23538 Lübeck, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Gillessen-Kaesbach
authors.affiliation: Institute of Neurogenetics, University of Lübeck, 23538?Lübeck, Germany.
authors.forename: Ana
authors.initials: A
authors.lastname: Westenberger
authors.affiliation: Institut fur Humangenetik, Universität zu Lübeck, 23538 Lübeck, Germany.
authors.forename: Dusanka
authors.initials: D
authors.lastname: Savic-Pavicevic
authors.affiliation: Institute of Neurogenetics, University of Lübeck, 23538?Lübeck, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Münchau
authors.affiliation: Centogene AG, 18057 Rostock, Germany.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Oprea
authors.affiliation: Institute of Neurogenetics, University of Lübeck, 23538?Lübeck, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Klein
authors.affiliation: Centogene AG, 18057 Rostock, Germany.|Centre for Human Molecular Genetics, Faculty of Biology, University of Belgrade, Belgrade, Serbia.
authors.forename: Arndt
authors.initials: A
authors.lastname: Rolfs
authors.affiliation: Department of Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Kirill A
authors.initials: KA
authors.lastname: Martemyanov
mesh_terms: D002648:Child; D002675:Child, Preschool; D002658:Developmental Disabilities / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D059472:Exome / Q000235:genetics; D005260:Female; D044387:GTP-Binding Protein beta Subunits / Q000235:genetics* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D020962:Heterotrimeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007223:Infant; D008297:Male; D020125:Mutation, Missense / Q000235:genetics*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D017447:Receptors, Dopamine D1 / Q000235:genetics / Q000378:metabolism
chemical_list: C516790:GNB1 protein, human; D044387:GTP-Binding Protein beta Subunits; D017447:Receptors, Dopamine D1; D020962:Heterotrimeric GTP-Binding Proteins