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Clin Sci (Lond). 2018 Dec 5;132(23):2483-2491. doi: 10.1042/CS20180732. Print 2018 Dec 12.

MIB1 mutations reduce Notch signaling activation and contribute to congenital heart disease.

Li B1,2,3, Yu L3, Liu D4, Yang X1,2, Zheng Y1,5, Gui Y3, Wang H6,2,3,7.

Author information

1
Obstetrics and Gynecology Hospital, State Key Laboratory of Genetic Engineering at School of Life Sciences, Institute of Reproduction and Development, Fudan University, Shanghai 200011, China.
2
NHC Key Lab of Reproduction (Shanghai Institute of Planned Parenthood Research), Collaborative Innovation Center of Genetics and Development, Fudan University, Shanghai 200032, China.
3
Children's Hospital, Fudan University, Shanghai 201102, China.
4
Co-innovation Center of Neuroregeneration, Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Nantong University, Nantong 226001, China.
5
Institute of Developmental Biology and Molecular Medicine, Fudan University, Shanghai 200433, China.
6
Obstetrics and Gynecology Hospital, State Key Laboratory of Genetic Engineering at School of Life Sciences, Institute of Reproduction and Development, Fudan University, Shanghai 200011, China wanghy@fudan.edu.cn.
7
The Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.

Abstract

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.

KEYWORDS:

Congenital heart disease (CHD); Mind bomb 1 (MIB1); Notch signaling pathway; Rare mutations

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