ArticleDisease models & mechanisms2022
Auriculocondylar syndrome 2 results from the dominant-negative action of PLCB4 variants.
Article in Disease models & mechanisms, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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9 citing papers in PubMed, 14 citations in OpenAlex.
- Trio-based GWAS reveals novel loci associated with different forms of isolated cleft lip.medRxiv : the preprint server for health sciences · 2026Article
- The Gq/11 family of Gα subunits is necessary and sufficient for lower jaw development.Development (Cambridge, England) · 2025Article
- Auriculocondylar syndrome 2 caused by a novel PLCB4 variant in a male Chinese neonate: A case report and review of the literature.Molecular genetics & genomic medicine · 2024Review
- Whole exome sequencing and polygenic assessment of a Swedish cohort with severe developmental language disorder.Human genetics · 2024Article
- Interaction between MARK3 (rs11623869), PLCB4 (rs6086746) and GEMIN2 (rs2277458) variants with bone mineral density and serum 25-hidroxivitamin D levels in Mexican Mestizo women.Frontiers in endocrinology · 2024Article
- Endothelin signaling in development.Development (Cambridge, England) · 2023Review
- Transcriptomic analysis reveals the role of SIX1 in mouse cranial neural crest patterning and bone development.Developmental dynamics : an official publication of the American Association of Anatomists · 2023Article
- Correspondence of Yolk Sac and Embryonic Genotypes in F0 Mouse CRISPants.Medical research archives · 2023Article
- Mandibulofacial dysostosis with alopecia results from ETAR gain-of-function mutations via allosteric effects on ligand binding.The Journal of clinical investigation · 2023Article
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Authors and funding
10 authors at 5 institutions in 1 country.
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Abstract
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.
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