The etiology of congenital heart defects (CHDs), which are among the most common human birth defects, is poorly understood because of its complex genetic architecture. Here, we show that two genes implicated in CHDs, Megf8 and Mgrn1, interact genetically and biochemically to regulate the strength of Hedgehog signaling in target cells. MEGF8, a transmembrane protein, and MGRN1, a RING superfamily E3 ligase, assemble to form a receptor-like ubiquitin ligase complex that catalyzes the ubiquitination and degradation of the Hedgehog pathway transducer Smoothened. Homozygous Megf8 and Mgrn1 mutations increased Smoothened abundance and elevated sensitivity to Hedgehog ligands. While mice heterozygous for loss-of-function Megf8 or Mgrn1 mutations were normal, double heterozygous embryos exhibited an incompletely penetrant syndrome of CHDs with heterotaxy. Thus, genetic interactions can arise from biochemical mechanisms that calibrate morphogen signaling strength, a conclusion broadly relevant for the many human diseases in which oligogenic inheritance is emerging as a mechanism for heritability.

先天性心脏缺陷 (CHD) 是最常见的人类出生缺陷之一，由于其复杂的遗传结构，其病因知之甚少。在这里，我们展示了与冠心病有关的两个基因，Megf8和Mgrn1，通过遗传和生化相互作用来调节靶细胞中 Hedgehog 信号的强度。跨膜蛋白 MEGF8 和 RING 超家族 E3 连接酶 MGRN1 组装形成受体样泛素连接酶复合物，催化 Hedgehog 通路转导器 Smoothened 的泛素化和降解。纯合子Megf8和Mgrn1突变增加了 Smoothened 丰度并提高了对 Hedgehog 配体的敏感性。虽然小鼠是Megf8功能丧失的杂合子或Mgrn1突变是正常的，双杂合子胚胎表现出具有异位性的 CHD 的不完全外显综合征。因此，遗传相互作用可能源于校准形态发生素信号强度的生化机制，这一结论与许多人类疾病广泛相关，在这些疾病中，寡基因遗传正在作为一种遗传机制出现。