biostudies-literatureDi Rocco MItalian National Institute of HealthNational Research CouncilNIH HHS929-941https://www.ebi.ac.uk/biostudies/studies/S-EPMC8947233biostudies-literatureUnknown31(6)Dominant GNAO1 mutations cause an emerging group of childhood-onset neurological disorders characterized by developmental delay, intellectual disability, movement disorders, drug-resistant seizures and neurological deterioration. GNAO1 encodes the α-subunit of an inhibitory GTP/GDP-binding protein regulating ion channel activity and neurotransmitter release. The pathogenic mechanisms underlying GNAO1-related disorders remain largely elusive and there are no effective therapies. Here, we assessed the functional impact of two disease-causing variants associated with distinct clinical features, c.139A > G (p.S47G) and c.662C > A (p.A221D), using Caenorhabditis elegans as a model organism. The c.139A > G change was introduced into the orthologous position of the C. elegans gene via CRISPR/Cas9Human molecular geneticsCaenorhabditis elegans provides an efficient drug screening platform for GNAO1-related disorders and highlights the potential role of caffeine in controlling dyskinesia.PMC8947233NUTR-AGE-FOE2019-DSB.AD004.2712020-2022_ISS20-0ab01a06bd2aP40 OD010440Caprini DLanza EBocchinfuso GFolli VLeuzzi VMartinelli SDi Rocco MFriedman JGalosi STosato FMartire ADi Schiavi EfalseCaenorhabditis elegans provides an efficient drug screening platform for GNAO1-related disorders and highlights the potential role of caffeine in controlling dyskinesia.Dominant GNAO1 mutations cause an emerging group of childhood-onset neurological disorders characterized by developmental delay, intellectual disability, movement disorders, drug-resistant seizures and neurological deterioration. GNAO1 encodes the α-subunit of an inhibitory GTP/GDP-binding protein regulating ion channel activity and neurotransmitter release. The pathogenic mechanisms underlying GNAO1-related disorders remain largely elusive and there are no effective therapies. Here, we assessed the functional impact of two disease-causing variants associated with distinct clinical features, c.139A > G (p.S47G) and c.662C > A (p.A221D), using Caenorhabditis elegans as a model organism. The c.139A > G change was introduced into the orthologous position of the C. elegans gene via CRISPR/Cas92022-01-01T00:00:00Z2022 Mar2026-05-30T20:56:45.313Z2025-04-04T10:01:51.94ZS-EPMC89472333462228210.1093/hmg/ddab296