{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T11:40:28Z","timestamp":1792410028736,"version":"4.4.0"},"reference-count":72,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2021,9,11]],"date-time":"2021-09-11T00:00:00Z","timestamp":1631318400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 DA048036"],"award-info":[{"award-number":["R01 DA048036"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 DA036596"],"award-info":[{"award-number":["R01 DA036596"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Bow Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,2,21]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>GNAO1 encephalopathy is a neurodevelopmental disorder with a spectrum of symptoms that include dystonic movements, seizures and developmental delay. While numerous GNAO1 mutations are associated with this disorder, the functional consequences of pathological variants are not completely understood. Here, we deployed the invertebrate C. elegans as a whole-animal behavioral model to study the functional effects of GNAO1 disorder-associated mutations. We tested several pathological GNAO1 mutations for effects on locomotor behaviors using a combination of CRISPR\/Cas9 gene editing and transgenic overexpression in vivo. We report that all three mutations tested (G42R, G203R and R209C) result in strong loss of function defects when evaluated as homozygous CRISPR alleles. In addition, mutations produced dominant negative effects assessed using both heterozygous CRISPR alleles and transgenic overexpression. Experiments in mice confirmed dominant negative effects of GNAO1 G42R, which impaired numerous motor behaviors. Thus, GNAO1 pathological mutations result in conserved functional outcomes across animal models. Our study further establishes the molecular genetic basis of GNAO1 encephalopathy, and develops a CRISPR-based pipeline for functionally evaluating mutations associated with neurodevelopmental disorders.<\/jats:p>","DOI":"10.1093\/hmg\/ddab235","type":"journal-article","created":{"date-parts":[[2021,9,9]],"date-time":"2021-09-09T12:24:41Z","timestamp":1631190281000},"page":"510-522","source":"Crossref","is-referenced-by-count":43,"title":["Genetic modeling of GNAO1 disorder delineates mechanisms of G\u03b1o dysfunction"],"prefix":"10.1093","volume":"31","author":[{"given":"Dandan","family":"Wang","sequence":"first","affiliation":[{"name":"Center for Integrative Brain Research, Seattle Children\u2019s Research Institute, Seattle, WA 98101, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Dao","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian S","family":"Muntean","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew C","family":"Giles","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirill A","family":"Martemyanov","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brock","family":"Grill","sequence":"additional","affiliation":[{"name":"Center for Integrative Brain Research, Seattle Children\u2019s Research Institute, Seattle, WA 98101, USA"},{"name":"Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA"},{"name":"Department of Pharmacology, University of Washington School of Medicine, Seattle, WA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,9,11]]},"reference":[{"key":"2022022310593087900_ref1","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/0968-0004(92)90005-T","article-title":"G proteins","volume":"17","author":"Hepler","year":"1992","journal-title":"Trends Biochem. 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