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Clin Sci (Lond). 2019 Jan 22;133(2):225-238. doi: 10.1042/CS20180842. Print 2019 Jan 31.

Rare mutations of ADAM17 from TOFs induce hypertrophy in human embryonic stem cell-derived cardiomyocytes via HB-EGF signaling.

Xie Y1,2, Ma A2, Wang B2, Peng R2,3, Jing Y2,4, Wang D5, Finnell RH6,7, Qiao B8, Wang Y9,10, Wang H11,2,3,12, Zheng Y13,3,4.

Author information

1
Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
2
Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, State Key Laboratory of Genetic Engineering at School of Life Sciences, Fudan University, Shanghai 200011, China.
3
Key Laboratory of Reproduction Regulation of NPFPC, Collaborative Innovation Center of Genetics and Development, Fudan University, Shanghai 200032, China.
4
Institute of Developmental Biology & Molecular Medicine, Fudan University, Shanghai 200433, China.
5
School of Life Sciences, Fudan University, Shanghai 200438, China.
6
Departments of Molecular and Cellular Biology and Medicine, Baylor College of Medicine, Houston, Texas 77030, USA.
7
Collaborative Innovation Center for Genetics & Development, School of Life Sciences, Fudan University, Shanghai 200438, China.
8
Institute of Cardiovascular Disease, General Hospital of Jinan Military Region, Jinan 250022, China.
9
MOE Key Laboratory of Contemporary Anthropology at School of Life Sciences, Fudan University, Shanghai 200438, China zhengyf@fudan.edu.cn ymw@fudan.edu.cn wanghy@fudan.edu.cn.
10
Zhongshan Hospital of Fudan University,180 Fenglin Road, Shanghai 200032, China.
11
Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China zhengyf@fudan.edu.cn ymw@fudan.edu.cn wanghy@fudan.edu.cn.
12
Children's Hospital of Fudan University, 399 Wanyuan Road, Shanghai 201102, China.
13
Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, State Key Laboratory of Genetic Engineering at School of Life Sciences, Fudan University, Shanghai 200011, China zhengyf@fudan.edu.cn ymw@fudan.edu.cn wanghy@fudan.edu.cn.

Abstract

Tetralogy of Fallot (TOF) is the most common cyanotic form of congenital heart defects (CHDs). The right ventricular hypertrophy is associated with the survival rate of patients with repaired TOF. However, very little is known concerning its genetic etiology. Based on mouse model studies, a disintergrin and metalloprotease 10/17 (ADAM10 and ADAM17) are the key enzymes for the NOTCH and ErbB pathways, which are critical pathways for heart development. Mutations in these two genes have not been previously reported in human TOF patients. In this study, we sequenced ADAM10 and ADAM17 in a Han Chinese CHD cohort comprised of 80 TOF patients, 286 other CHD patients, and 480 matched healthy controls. Three missense variants of ADAM17 were only identified in 80 TOF patients, two of which (Y42D and L659P) are novel and not found in the Exome Aggregation Consortium (ExAC) database. Point mutation knock-in (KI) and ADAM17 knock-out (KO) human embryonic stem cells (hESCs) were generated by CRISPR/Cas9 and programmed to differentiate into cardiomyocytes (CMs). Y42D or L659P KI cells or complete KO cells all developed hypertrophy with disorganized sarcomeres. RNA-seq results showed that phosphatidylinositide 3-kinases/protein kinase B (PI3K/Akt), which is downstream of epidermal growth factor receptor (EGFR) signaling, was affected in both ADAM17 KO and KI hESC-CMs. In vitro experiments showed that these two mutations are loss-of-function mutations in shedding heparin-binding EGF-like growth factor (HB-EGF) but not NOTCH signaling. Our results revealed that CM hypertrophy in TOF could be the result of mutations in ADAM17 which affects HB-EGF/ErbB signaling.

KEYWORDS:

ADAM17; Tetrology of Fallot; cardiac hypertrophy; cardiomyocytes; hESCs; rare mutation

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