MIB1 mutations reduce Notch signaling activation and contribute to congenital heart disease.
MIB1 mutations reduce Notch signaling activation and contribute to congenital heart disease.
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MIB1突变减少Notch信号激活并导致先天性心脏病
DOI：
10.1042/cs20180732
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发表时间：
2018-12-12
期刊：
影响因子：
--
通讯作者：
Wang H
中科院分区：
文献类型：
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作者：
Li B;Yu L;Liu D;Yang X;Zheng Y;Gui Y;Wang H
先天性心脏病（CHD）是人类最常见的出生缺陷之一，但尽管经过数十年的研究，其遗传病因仍在很大程度上未知。Notch信号通路在胚胎心脏发生中起关键作用。思维炸弹1（Mib 1）是通过促进Notch配体的泛素化、内吞作用和随后的激活来激活Notch信号通路的重要蛋白。先前的研究表明，Mib 1基因敲除小鼠完全消除了Notch信号，导致心脏畸形。然而，MIB1的功能及其潜在的致病突变在人类CHD中的研究很少。在这项研究中，我们从417名中国汉族CHD患者中发现了MIB 1的四种新型非同义杂合罕见突变。以下生物化学分析显示，突变p.T312K fs*55和p.W271G显著耗尽MIB1的功能，导致较低水平的JAGGED 1（JAG 1）泛素化和Notch信号传导诱导。我们的研究结果表明，MIB1的病理变异可能有助于冠心病的发生，在Notch信号通路的背景下，冠心病的遗传机制提供了新的光。
Congenital heart disease (CHD) is one of the most common birth defects in humans, but its genetic etiology remains largely unknown despite decades of research. The Notch signaling pathway plays critical roles in embryonic cardiogenesis. Mind bomb 1 (Mib1) is a vital protein that activates the Notch signaling pathway through promoting ubiquitination, endocytosis and subsequent activation of Notch ligands. Previous studies show that Mib1 knockout in mice completely abolishes Notch signaling, leading to cardiac deformity. However, the function of MIB1 and its potential disease-causing mutations are poorly studied in human CHD. In this research, we identified four novel non-synonymous heterozygous rare mutations of MIB1 from 417 Han Chinese CHD patients. The following biochemical analyses revealed that mutations p.T312K fs*55 and p.W271G significantly deplete MIB1’s function, resulting in a lower level of JAGGED1 (JAG1) ubiquitination and Notch signaling induction. Our results suggest that pathologic variants in MIB1 may contribute to CHD occurrence, shedding new light on the genetic mechanism of CHD in the context of the Notch signaling pathway.