{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T14:47:29Z","timestamp":1791384449309,"version":"4.3.3"},"reference-count":24,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2023,4,25]],"date-time":"2023-04-25T00:00:00Z","timestamp":1682380800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"US Dept of Defense Medical Research Program Discovery","award":["W81XWH2110061"],"award-info":[{"award-number":["W81XWH2110061"]}]},{"name":"2020 Sturge\u2013Weber Foundation Catalyst","award":["T32 HL007101-45"],"award-info":[{"award-number":["T32 HL007101-45"]}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,8,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Sturge\u2013Weber Syndrome (SWS) is a sporadic (non-inherited) syndrome characterized by capillary vascular malformations in the facial skin, leptomeninges, or the choroid. A hallmark feature is the mosaic nature of the phenotype. SWS is caused by a somatic mosaic mutation in the GNAQ gene (p.R183Q), leading to activation of the G protein, G\u03b1q. Decades ago, Rudolf Happle hypothesized SWS as an example of \u201cparadominant inheritance\u201d, that is, a \u201clethal gene (mutation) surviving by mosaicism\u201d. He predicted that the \u201cpresence of the mutation in the zygote will lead to death of the embryo at an early stage of development\u201d. We have created a mouse model for SWS using gene targeting to conditionally express the GNAQ p.R183Q mutation. We have employed two different Cre-drivers to examine the phenotypic effects of expression of this mutation at different levels and stages of development. As predicted by Happle, global, ubiquitous expression of this mutation in the blastocyst stage results in 100% embryonic death. The majority of these developing embryos show vascular defects consistent with the human vascular phenotype. By contrast, global but mosaic expression of the mutation enables a fraction of the embryos to survive, but those that survive to birth and beyond do not exhibit obvious vascular defects. These data validate Happle's paradominant inheritance hypothesis for SWS and suggest the requirement of a tight temporal and developmental window of mutation expression for the generation of the vascular phenotype. Furthermore, these engineered murine alleles provide the template for the development of a mouse model of SWS that acquires the somatic mutation during embryonic development, but permits the embryo to progress to live birth and beyond, so that postnatal phenotypes can also be investigated. These mice could then also be employed in pre-clinical studies of novel therapies.<\/jats:p>","DOI":"10.1093\/genetics\/iyad077","type":"journal-article","created":{"date-parts":[[2023,4,25]],"date-time":"2023-04-25T18:26:14Z","timestamp":1682447174000},"source":"Crossref","is-referenced-by-count":27,"title":["Developmental expression of the Sturge\u2013Weber syndrome-associated genetic mutation in <i>Gnaq<\/i>: a formal test of Happle's paradominant inheritance hypothesis"],"prefix":"10.1093","volume":"224","author":[{"given":"Sarah E","family":"Wetzel-Strong","sequence":"first","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, Duke University School of Medicine , Durham, NC 27710 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Galeffi","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, Duke University School of Medicine , Durham, NC 27710 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Benavides","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, Duke University School of Medicine , Durham, NC 27710 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary","family":"Patrucco","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, Duke University School of Medicine , Durham, NC 27710 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica L","family":"Bullock","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, Duke University School of Medicine , Durham, NC 27710 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carol J","family":"Gallione","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, Duke University School of Medicine , Durham, NC 27710 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han Kyu","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, Duke University School of Medicine , Durham, NC 27710 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas A","family":"Marchuk","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, Duke University School of Medicine , Durham, NC 27710 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,4,25]]},"reference":[{"issue":"4","key":"2024022419374069800_iyad077-B1","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1007\/s10456-022-09841-w","article-title":"A novel somatic mutation in GNAQ in a capillary malformation provides insight into molecular 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