Auriculocondylar syndrome 2 results from the dominant-negative action of PLCB4 variants
Auriculocondylar syndrome 2 (ARCND2) is a rare autosomal dominant craniofacial malformation syndrome linked to multiple genetic variants in the coding sequence of phospholipase C β4 (PLCB4). PLCB4 is a direct signaling effector of the endothelin receptor type A (EDNRA)-Gq/11 pathway, which establish...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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The Company of Biologists
2022-04-01
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| Series: | Disease Models & Mechanisms |
| Subjects: | |
| Online Access: | http://dmm.biologists.org/content/15/4/dmm049320 |
| _version_ | 1811257849633832960 |
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| author | Stanley M. Kanai Caleb Heffner Timothy C. Cox Michael L. Cunningham Francisco A. Perez Aaron M. Bauer Philip Reigan Cristan Carter Stephen A. Murray David E. Clouthier |
| author_facet | Stanley M. Kanai Caleb Heffner Timothy C. Cox Michael L. Cunningham Francisco A. Perez Aaron M. Bauer Philip Reigan Cristan Carter Stephen A. Murray David E. Clouthier |
| author_sort | Stanley M. Kanai |
| collection | DOAJ |
| description | Auriculocondylar syndrome 2 (ARCND2) is a rare autosomal dominant craniofacial malformation syndrome linked to multiple genetic variants in the coding sequence of phospholipase C β4 (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. This article has an associated First Person interview with the first author of the paper. |
| first_indexed | 2024-04-12T18:03:58Z |
| format | Article |
| id | doaj.art-1018cf0b961340698266dbc93ce8cfff |
| institution | Directory Open Access Journal |
| issn | 1754-8403 1754-8411 |
| language | English |
| last_indexed | 2024-04-12T18:03:58Z |
| publishDate | 2022-04-01 |
| publisher | The Company of Biologists |
| record_format | Article |
| series | Disease Models & Mechanisms |
| spelling | doaj.art-1018cf0b961340698266dbc93ce8cfff2022-12-22T03:22:02ZengThe Company of BiologistsDisease Models & Mechanisms1754-84031754-84112022-04-0115410.1242/dmm.049320049320Auriculocondylar syndrome 2 results from the dominant-negative action of PLCB4 variantsStanley M. Kanai0Caleb Heffner1Timothy C. Cox2Michael L. Cunningham3Francisco A. Perez4Aaron M. Bauer5Philip Reigan6Cristan Carter7Stephen A. Murray8David E. Clouthier9 Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA The Jackson Laboratory, Bar Harbor, ME 04609, USA Departments of Oral and Craniofacial Sciences and Pediatrics, University of Missouri-Kansas City, Kansas City, MO 64108, USA University of Washington, Department of Pediatrics, Division of Craniofacial Medicine and Seattle Children's Craniofacial Center, Seattle, WA 98105, USA University of Washington, Department of Radiology and Seattle Children's Hospital, Seattle, WA 98105, USA Department of Biology, Villanova University, Villanova, PA 19085, USA Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA The Jackson Laboratory, Bar Harbor, ME 04609, USA Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA Auriculocondylar syndrome 2 (ARCND2) is a rare autosomal dominant craniofacial malformation syndrome linked to multiple genetic variants in the coding sequence of phospholipase C β4 (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. This article has an associated First Person interview with the first author of the paper.http://dmm.biologists.org/content/15/4/dmm049320craniofacialg proteinneural crest cellcrisprevolutionmice |
| spellingShingle | Stanley M. Kanai Caleb Heffner Timothy C. Cox Michael L. Cunningham Francisco A. Perez Aaron M. Bauer Philip Reigan Cristan Carter Stephen A. Murray David E. Clouthier Auriculocondylar syndrome 2 results from the dominant-negative action of PLCB4 variants Disease Models & Mechanisms craniofacial g protein neural crest cell crispr evolution mice |
| title | Auriculocondylar syndrome 2 results from the dominant-negative action of PLCB4 variants |
| title_full | Auriculocondylar syndrome 2 results from the dominant-negative action of PLCB4 variants |
| title_fullStr | Auriculocondylar syndrome 2 results from the dominant-negative action of PLCB4 variants |
| title_full_unstemmed | Auriculocondylar syndrome 2 results from the dominant-negative action of PLCB4 variants |
| title_short | Auriculocondylar syndrome 2 results from the dominant-negative action of PLCB4 variants |
| title_sort | auriculocondylar syndrome 2 results from the dominant negative action of plcb4 variants |
| topic | craniofacial g protein neural crest cell crispr evolution mice |
| url | http://dmm.biologists.org/content/15/4/dmm049320 |
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