An intronic GNAO1 variant leading to in-frame insertion cause movement disorder controlled by deep brain stimulation.

GNAO1 variants are associated with a wide range of neurodevelopmental disorders including epileptic encephalopathies and movement disorders. It has been reported that some GNAO1 variants are associated with movement disorders, and the 207-246 amino acid region was proposed as a mutational hotspot. Here, we report an intronic variant (NM_020988.3:c.724-8G>A) in GNAO1 in a Japanese girl who showed mild developmental delay and movement disorders including dystonia and myoclonus. Her movement disorders were improved by deep brain stimulation treatment as previously reported. This variant has been recurrently reported in four patients and was transmitted from her mother who possessed the variant as low-prevalent mosaicism. Using RNA extracted from lymphoblastoid cells derived from the patient, we demonstrated that the variant caused abnormal splicing of in-frame 6-bp intronic retention, leading to 2 amino acid insertion (p.Thr241_Asn242insProGln). Immunoblotting and immunostaining using WT and mutant GNAO1 vectors showed no significant differences in protein expression levels, but the cellular localization pattern of this mutant was partially shifted to the cytoplasm whereas WT was exclusively localized in the cellular membrane. Our report first clarified abnormal splicing and resulting mutant protein caused by the c.724-8G>A variant.