Document Type

Article

Publication Date

4-1-2022

Publication Title

Dis Model Mech

Keywords

JMG, Animals, Ear, Ear Diseases, Humans, Mice, Neural Crest, Phenotype, Phospholipase C beta

JAX Source

Dis Model Mech 2022 Apr 1; 15(4):dmm049320

Volume

15

Issue

4

ISSN

1754-8411

PMID

35284927

DOI

https://doi.org/10.1242/dmm.049320

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.

Comments

This is an Open Access article distributed under the terms of the Creative Commons Attribution License.

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