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

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 ExAC database. Point mutation knock-in (KI) and ADAM17 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 PI3K/Akt, which is down stream of 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 HB-EGF but not NOTCH signaling. Our results revealed that cardiomyocyte hypertrophy in TOF could be the result of mutations in ADAM17 which affects HB-EGF/ErbB signaling.

Source: Clinical Science - January 4, 2019 Category: Biomedical Science Authors: Xie, Y., Ma, A., Wang, B., Peng, R., Jing, Y., Wang, D., Finnell, R. H., Qiao, B., Wang, Y., Wang, H., Zheng, Y. Tags: PublishAheadOfPrint Source Type: research