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

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Science Signaling  12 Apr 2016:
Vol. 9, Issue 423, pp. ra37
DOI: 10.1126/scisignal.aad2429

i gets in the way of Gαq

Signaling by G protein–coupled receptors (GPCRs) regulates various aspects of development and adult physiology, and mutations in GPCR signaling pathway components cause disease. Some patients with auriculo-condylar syndrome (ACS), who have defects in craniofacial development, have mutations in the heterotrimeric G protein subunit Gαi3. Developmental analysis of transfected Xenopus embryos and biochemical analysis in mammalian cells revealed that the Gαi3 mutations associated with ACS enable Gαi3 to bind inappropriately to the endothelin receptor ETAR and block the binding of another G protein, Gαq/11. Although able to bind ETAR, Gαi3 mutants lacked enzymatic activity, thereby preventing intracellular propagation of the endothelin signal. The findings show that dominant-negative mutations in one G protein can impair another and cause disease.


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 Gαq/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 Gαi3, 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 Gαi3 mutants. We found that ACS-associated mutations in GNAI3 produce dominant-negative Gαi3 mutant proteins that couple to ETAR but cannot bind and hydrolyze guanosine triphosphate, resulting in the prevention of endothelin-mediated activation of Gαq/11 and PLC. Thus, ACS is caused by functionally dominant-negative mutations in a heterotrimeric G protein subunit.

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