{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T09:33:17Z","timestamp":1790760797440,"version":"4.1.0"},"reference-count":95,"publisher":"The Company of Biologists","issue":"4","license":[{"start":{"date-parts":[[2022,4,29]],"date-time":"2022-04-29T00:00:00Z","timestamp":1651190400000},"content-version":"vor","delay-in-days":28,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["DE025862-03S1"],"award-info":[{"award-number":["DE025862-03S1"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["OD024941"],"award-info":[{"award-number":["OD024941"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Jean Renny Craniofacial Endowment"},{"name":"Stowers Family Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,4,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n               <jats:p>Auriculocondylar syndrome 2 (ARCND2) is a rare autosomal dominant craniofacial malformation syndrome linked to multiple genetic variants in the coding sequence of phospholipase C \u03b24 (PLCB4). PLCB4 is a direct signaling effector of the endothelin receptor type A (EDNRA)-Gq\/11 pathway, which establishes the identity of neural crest cells (NCCs) that form lower jaw and middle ear structures. However, the functional consequences of PLCB4 variants on EDNRA signaling is not known. Here, we show, using multiple signaling reporter assays, that known PLCB4 variants resulting from missense mutations exert a dominant-negative interference over EDNRA signaling. In addition, using CRISPR\/Cas9, we find that F0 mouse embryos modeling one PLCB4 variant have facial defects recapitulating those observed in hypomorphic Ednra mouse models, including a bone that we identify as an atavistic change in the posterior palate\/oral cavity. Remarkably, we have identified a similar osseous phenotype in a child with ARCND2. Our results identify the disease mechanism of ARCND2, demonstrate that the PLCB4 variants cause craniofacial differences and illustrate how minor changes in signaling within NCCs may have driven evolutionary changes in jaw structure and function.<\/jats:p>\n               <jats:p>This article has an associated First Person interview with the first author of the paper.<\/jats:p>","DOI":"10.1242\/dmm.049320","type":"journal-article","created":{"date-parts":[[2022,3,14]],"date-time":"2022-03-14T08:43:17Z","timestamp":1647247397000},"source":"Crossref","is-referenced-by-count":14,"title":["Auriculocondylar syndrome 2 results from the dominant-negative action of <i>PLCB4<\/i> variants"],"prefix":"10.1242","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9074-0624","authenticated-orcid":false,"given":"Stanley M.","family":"Kanai","sequence":"first","affiliation":[{"name":"Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caleb","family":"Heffner","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory, Bar Harbor, ME 04609, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8015-5528","authenticated-orcid":false,"given":"Timothy C.","family":"Cox","sequence":"additional","affiliation":[{"name":"Departments of Oral and Craniofacial Sciences and Pediatrics, University of Missouri-Kansas City, Kansas City, MO 64108, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2277-654X","authenticated-orcid":false,"given":"Michael L.","family":"Cunningham","sequence":"additional","affiliation":[{"name":"University of Washington, Department of Pediatrics, Division of Craniofacial Medicine and Seattle Children's Craniofacial Center, Seattle, WA 98105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8456-5209","authenticated-orcid":false,"given":"Francisco A.","family":"Perez","sequence":"additional","affiliation":[{"name":"University of Washington, Department of Radiology and Seattle Children's Hospital, Seattle, WA 98105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6839-8025","authenticated-orcid":false,"given":"Aaron M.","family":"Bauer","sequence":"additional","affiliation":[{"name":"Department of Biology, Villanova University, Villanova, PA 19085, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip","family":"Reigan","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristan","family":"Carter","sequence":"additional","affiliation":[{"name":"Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0594-1702","authenticated-orcid":false,"given":"Stephen A.","family":"Murray","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory, Bar Harbor, ME 04609, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2008-477X","authenticated-orcid":false,"given":"David E.","family":"Clouthier","sequence":"additional","affiliation":[{"name":"Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2022,4,29]]},"reference":[{"key":"2022042910223488600_DMM049320C1","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1387\/ijdb.062237ma","article-title":"Fate of cranial neural crest cells during craniofacial development in endothelin-A receptor-deficient mice","volume":"51","author":"Abe","year":"2007","journal-title":"Int. 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