Novel variants in GNAI3 associated with auriculocondylar syndrome strengthen a common dominant negative effect

Tavares, Vanessa Luiza Romanelli; Gordon, Christopher T.; Zechi-Ceide, Roseli Maria; Kokitsu-Nakata, Nancy Mizue; Voisin, Norine; Tan, Tiong Yang; Heggie, Andrew A; Vendramini-Pittoli, Siulan; Propst, Evan J.; Papsin, Blake C.; Torres, Tatiana Teixeira; Buermans, Henk P.J.; Capelo, Luciane Portas; Dunnen, Johan T. den; Guion‐Almeida, Maria Leine; Lyonnet, Stanislas; Amiel, Jeanne; Passos‐Bueno, Maria Rita

doi:10.1038/ejhg.2014.132

Cited by 29 publications

(28 citation statements)

References 19 publications

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“…Another argument against the MFDA variants being entirely loss of function is the phenotype of ACS and isolated question mark ears, both of which result from lossof-function or dominant-negative variants in EDN1, PLCB4, and GNAI3, encoding components of the EDNRA pathway. 8,32,33 In ACS the lower jaw is typically extremely hypoplastic and the upper jaw is essentially normal. Similarly, the lower jaw of Ednra-null mice is more severely affected than the upper jaw.…”

Section: E135 Ednra Lacz/+mentioning

confidence: 99%

Mutations in the Endothelin Receptor Type A Cause Mandibulofacial Dysostosis with Alopecia

Gordon

Weaver

Zechi-Ceide

et al. 2015

The American Journal of Human Genetics

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The endothelin receptor type A (EDNRA) signaling pathway is essential for the establishment of mandibular identity during development of the first pharyngeal arch. We report four unrelated individuals with the syndrome mandibulofacial dysostosis with alopecia (MFDA) who have de novo missense variants in EDNRA. Three of the four individuals have the same substitution, p.Tyr129Phe. Tyr129 is known to determine the selective affinity of EDNRA for endothelin 1 (EDN1), its major physiological ligand, and the p.Tyr129Phe variant increases the affinity of the receptor for EDN3, its non-preferred ligand, by two orders of magnitude. The fourth individual has a somatic mosaic substitution, p.Glu303Lys, and was previously described as having Johnson-McMillin syndrome. The zygomatic arch of individuals with MFDA resembles that of mice in which EDNRA is ectopically activated in the maxillary prominence, resulting in a maxillary to mandibular transformation, suggesting that the p.Tyr129Phe variant causes an EDNRA gain of function in the developing upper jaw. Our in vitro and in vivo assays suggested complex, context-dependent effects of the EDNRA variants on downstream signaling. Our findings highlight the importance of finely tuned regulation of EDNRA signaling during human craniofacial development and suggest that modification of endothelin receptor-ligand specificity was a key step in the evolution of vertebrate jaws.

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Section: E135 Ednra Lacz/+mentioning

confidence: 99%

Mutations in the Endothelin Receptor Type A Cause Mandibulofacial Dysostosis with Alopecia

Gordon

Weaver

Zechi-Ceide

et al. 2015

The American Journal of Human Genetics

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“…Auriculo-Condylar Syndrome (ACS) (11–13) is a rare condition that impairs craniofacial development. Evidence from genetic studies in humans and animal models indicates that ACS is caused by disruption of an endothelin type A receptor (ET A R)→ Gα→PLC pathway that induces the expression of genes encoding the distalless homeobox (DLX) transcription factors DLX5 and DLX6 required for specification and patterning of neural crest cells during craniofacial development (14).…”

Section: Introductionmentioning

confidence: 99%

“…Five autosomal dominant mutations in Gαi3 have been found in type I ACS (11–13). All five mutations affect conserved amino acid positions that cluster within the nucleotide binding pocket (Fig.…”

Section: Introductionmentioning

confidence: 99%

“…S1). It has been speculated that ACS-associated Gα i3 mutants may behave as dominant-negatives (meaning it interferes with the function of the normal gene product) or as constitutively active G proteins (11, 13, 14). However, none of these hypotheses or the possibility of acting as loss-of-function mutants leading to haploinsuficiency have been formally tested.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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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 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. Here, 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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“…Many craniofacial syndromes are caused by defects in signaling pathways that pattern the cranial neural crest cells (CNCCs) along the dorsal-ventral (D/V) axis. For example, Auriculocondylar syndrome is caused by impaired Endothelin-1 (Edn1) signaling [4–6] and Alagille syndrome is caused by defects in Jagged (Jag)-Notch signaling [7, 8]. The BMP, Edn1, and Jag1b pathways intersect because BMP signaling is required for ventral edn1 expression that, in turn, restricts jag1b to dorsal CNCC territory [9–11].…”

Section: Introductionmentioning

confidence: 99%

Wdr68 Mediates Dorsal and Ventral Patterning Events for Craniofacial Development

et al. 2016

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Birth defects are among the leading causes of infant mortality and contribute substantially to illness and long-term disability. Defects in Bone Morphogenetic Protein (BMP) signaling are associated with cleft lip/palate. Many craniofacial syndromes are caused by defects in signaling pathways that pattern the cranial neural crest cells (CNCCs) along the dorsal-ventral axis. For example, auriculocondylar syndrome is caused by impaired Endothelin-1 (Edn1) signaling, and Alagille syndrome is caused by defects in Jagged-Notch signaling. The BMP, Edn1, and Jag1b pathways intersect because BMP signaling is required for ventral edn1 expression that, in turn, restricts jag1b to dorsal CNCC territory. In zebrafish, the scaffolding protein Wdr68 is required for edn1 expression and subsequent formation of the ventral Meckel’s cartilage as well as the dorsal Palatoquadrate. Here we report that wdr68 activity is required between the 17-somites and prim-5 stages, that edn1 functions downstream of wdr68, and that wdr68 activity restricts jag1b, hey1, and grem2 expression from ventral CNCC territory. Expression of dlx1a and dlx2a was also severely reduced in anterior dorsal and ventral 1st arch CNCC territory in wdr68 mutants. We also found that the BMP agonist isoliquiritigenin (ISL) can partially rescue lower jaw formation and edn1 expression in wdr68 mutants. However, we found no significant defects in BMP reporter induction or pSmad1/5 accumulation in wdr68 mutant cells or zebrafish. The Transforming Growth Factor Beta (TGF-β) signaling pathway is also known to be important for craniofacial development and can interfere with BMP signaling. Here we further report that TGF-β interference with BMP signaling was greater in wdr68 mutant cells relative to control cells. To determine whether interference might also act in vivo, we treated wdr68 mutant zebrafish embryos with the TGF-β signaling inhibitor SB431542 and found partial rescue of edn1 expression and craniofacial development. While ISL treatment failed, SB431542 partially rescued dlx2a expression in wdr68 mutants. Together these findings reveal an indirect role for Wdr68 in the BMP-Edn1-Jag1b signaling hierarchy and dorso-anterior expression of dlx1a/2a.

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Novel variants in GNAI3 associated with auriculocondylar syndrome strengthen a common dominant negative effect

Cited by 29 publications

References 19 publications

Mutations in the Endothelin Receptor Type A Cause Mandibulofacial Dysostosis with Alopecia

Mutations in the Endothelin Receptor Type A Cause Mandibulofacial Dysostosis with Alopecia

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

Wdr68 Mediates Dorsal and Ventral Patterning Events for Craniofacial Development

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