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A ubiquitin-based mechanism for the oligogenic inheritance of heterotaxy and heart defects
bioRxiv - Developmental Biology Pub Date : 2020-05-26 , DOI: 10.1101/2020.05.25.113944
Jennifer H. Kong , Cullen B. Young , Ganesh V. Pusapati , Chandni B. Patel , Sebastian Ho , Arunkumar Krishnan , Jiuann-Huey Ivy Lin , William Devine , Anne Moreau de Bellaing , Tejas S. Athni , L. Aravind , Teresa M. Gunn , Cecilia W. Lo , Rajat Rohatgi

The etiology of congenital heart defects (CHDs), amongst the most common human birth defects, is poorly understood partly because of its complex genetic architecture. Here we show that two genes previously implicated in CHDs, Megf8 and Mgrn1, interact genetically and biochemically to regulate the strength of Hedgehog signaling in target cells. MEGF8, a single-pass transmembrane protein, and MGRN1, a RING superfamily E3 ligase, assemble to form a transmembrane 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 between components of a receptor-like ubiquitin ligase complex that tunes morphogen signaling strength can cause a birth defect syndrome inherited in an oligogenic pattern.

中文翻译:

基于泛素的异源性和心脏缺陷寡聚遗传机制

在人类最常见的出生缺陷中,先天性心脏缺陷(CHD)的病因学知之甚少,部分原因是其复杂的遗传结构。在这里,我们显示了先前与冠心病有关的两个基因,Megf8和Mgrn1,在基因和生物化学上相互作用,以调节靶细胞中刺猬信号的强度。单通道跨膜蛋白MEGF8和RING超家族E3连接酶MGRN1组装形成跨膜遍在蛋白连接酶复合物,该复合物催化Hedgehog信号转导子Smoothed的泛素化和降解。纯合的Megf8和Mgrn1突变增加了平滑的丰度并提高了对刺猬配体的敏感性。虽然功能缺失的Megf8或Mgrn1突变杂合的小鼠是正常的,双杂合子胚胎表现出CHD的不完全渗透综合征和异源性。因此,调节形态发生子信号强度的受体样泛素连接酶复合物的成分之间的遗传相互作用会导致以寡聚模式遗传的先天缺陷综合症。
更新日期:2020-05-26
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