Craniofacial morphogenesis is regulated in part by signaling from the Endothelin receptor type A (EDNRA). Pathogenic variants in EDNRA signaling pathway components EDNRA, GNAI3, PCLB4, and EDN1 cause Mandibulofacial Dysostosis with Alopecia (MFDA), Auriculocondylar syndrome (ARCND) 1, 2, and 3, respectively. However, cardiovascular development is normal in MFDA and ARCND individuals, unlike Ednra knockout mice. One explanation may be that partial EDNRA signaling remains in MFDA and ARCND, as mice with reduced, but not absent, EDNRA signaling also lack a cardiovascular phenotype. Here we report an individual with craniofacial and cardiovascular malformations mimicking the Ednra -/- mouse phenotype, including a distinctive micrognathia with microstomia and a hypoplastic aortic arch. Exome sequencing found a novel homozygous missense variant in EDNRA (c.1142A>C; p.Q381P). Bioluminescence resonance energy transfer assays revealed that this amino acid substitution in helix 8 of EDNRA prevents recruitment of G proteins to the receptor, abrogating subsequent receptor activation by its ligand, Endothelin-1. This homozygous variant is thus the first reported loss-of-function EDNRA allele, resulting in a syndrome we have named Oro-Oto-Cardiac Syndrome. Further, our results illustrate that EDNRA signaling is required for both normal human craniofacial and cardiovascular development, and that limited EDNRA signaling is likely retained in ARCND and MFDA individuals. This work illustrates a straightforward approach to identifying the functional consequence of novel genetic variants in signaling molecules associated with malformation syndromes.

中文翻译：

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A 型内皮素受体功能丧失会导致 Oro-Oto-Cardiac 综合征。


颅面形态发生部分受到 A 型内皮素受体 (EDNRA) 信号的调节。 EDNRA 信号通路组件 EDNRA、GNAI3、PCLB4 和 EDN1 的致病变异分别导致下颌面发育不全伴脱发 (MFDA)、耳髁综合征 (ARCND) 1、2 和 3。然而，与 Ednra 基因敲除小鼠不同，MFDA 和 ARCND 个体的心血管发育是正常的。一种解释可能是 MFDA 和 ARCND 中保留了部分 EDNRA 信号传导，因为 EDNRA 信号传导减少但并非不存在的小鼠也缺乏心血管表型。在这里，我们报告了一个患有模仿 Ednra -/- 小鼠表型的颅面和心血管畸形的个体，包括具有小口和发育不全的主动脉弓的独特小下颌。外显子组测序在 EDNRA 中发现了一种新的纯合错义变异（c.1142A>C；p.Q381P）。生物发光共振能量转移测定表明，EDNRA 螺旋 8 中的这种氨基酸取代可防止 G 蛋白募集到受体，从而消除其配体 Endothelin-1 随后的受体激活。因此，这种纯合变异体是第一个报道的功能丧失的 EDNRA 等位基因，导致了一种我们命名为 Oro-Oto-Cardiac 综合征的综合征。此外，我们的结果表明，正常人类颅面和心血管发育都需要 EDNRA 信号传导，并且 ARCND 和 MFDA 个体中可能保留有限的 EDNRA 信号传导。这项工作展示了一种直接的方法来识别与畸形综合征相关的信号分子中新的遗传变异的功能后果。