RESUMEN
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 Gß1 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 Gßγ with Gα. Signaling properties of G protein complexes carrying mutant Gß1 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.
Asunto(s)
Discapacidades del Desarrollo/genética , Subunidades beta de la Proteína de Unión al GTP/genética , Mutación Missense/genética , Neuronas/metabolismo , Niño , Preescolar , Discapacidades del Desarrollo/metabolismo , Discapacidades del Desarrollo/patología , Exoma/genética , Femenino , Subunidades beta de la Proteína de Unión al GTP/metabolismo , Regulación del Desarrollo de la Expresión Génica , Proteínas de Unión al GTP Heterotriméricas/genética , Proteínas de Unión al GTP Heterotriméricas/metabolismo , Humanos , Lactante , Masculino , Neuronas/patología , Unión Proteica , Receptores de Dopamina D1/genética , Receptores de Dopamina D1/metabolismoRESUMEN
Recently, exome sequencing has extended our knowledge of genetic causes of developmental delay through identification of de novo, germline mutations in the guanine nucleotide-binding protein, beta 1 (GNB1) in 13 patients with neurodevelopmental disability and a wide range of additional symptoms and signs including hypotonia in 11 and seizures in 10 of the patients. Limb/arm dystonia was found in 2 patients.(1).