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Sci Signal April 12, 2016; 9 (423): ra37.

Dominant-negative Gα subunits are a mechanism of dysregulated heterotrimeric G protein signaling in human disease.

Marivin A , Leyme A , Parag-Sharma K , DiGiacomo V , Cheung AY , Nguyen LT , Dominguez I , Garcia-Marcos M .

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 (ET(A)R), which is mediated by the G protein (heterotrimeric guanine nucleotide-binding protein) subunit Gα(q/11) and subsequently phospholipase C (PLC), impairs neural crest cell differentiation that is required for normal craniofacial development. Some ACS patients have mutations inGNAI3, which encodes Gα(i3), but it is unknown whether this G protein has a role within the ET(A)R 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 Gα(i3) mutants. We found that ACS-associated mutations in GNAI3 produce dominant-negative Gα(i3) mutant proteins that couple to ET(A)R but cannot bind and hydrolyze guanosine triphosphate, resulting in the prevention of endothelin-mediated activation of Gα(q/11) and PLC. Thus, ACS is caused by functionally dominant-negative mutations in a heterotrimeric G protein subunit.

PubMed ID: 27072656
PMC ID: PMC4870087
Article link: Sci Signal
Grant support: [+]
Genes referenced: acss2.2 gnai3

References [+] :
Barren, Mechanisms of dominant negative G-protein alpha subunits. 2007, Pubmed

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