Journal
SCIENCE SIGNALING
Volume 9, Issue 423, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scisignal.aad2429
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Funding
- NIH [R01GM108733, R01GM112631, R01GM098367]
- American Cancer Society [RSG-13-362-01-TBE]
- American Heart Association [10GRNT3010038]
- Hartwell Foundation
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Auriculo-condylar syndrome (ACS), a rare condition that impairs craniofacial development, is caused by mutations in a G protein-coupled receptor (GPCR) signaling pathway. In mice, disruption of signaling by the endothelin type A receptor (ETAR), which is mediated by the G protein (heterotrimeric guanine nucleotide-binding protein) subunit G alpha(q/11) and subsequently phospholipase C (PLC), impairs neural crest cell differentiation that is required for normal craniofacial development. Some ACS patients have mutations in GNAI3, which encodes G alpha(i3), but it is unknown whether this G protein has a role within the ETAR pathway. We used a Xenopus model of vertebrate development, in vitro biochemistry, and biosensors of G protein activity in mammalian cells to systematically characterize the phenotype and function of all known ACS-associated G alpha(i3) mutants. We found that ACS-associated mutations in GNAI3 produce dominant-negative G alpha(i3) mutant proteins that couple to ETAR but cannot bind and hydrolyze guanosine triphosphate, resulting in the prevention of endothelin-mediated activation of G alpha(q/11) and PLC. Thus, ACS is caused by functionally dominant-negative mutations in a heterotrimeric G protein subunit.
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