Extracellular Matrix Disorganization Caused by ADAMTS16 Deficiency Leads to Bicuspid Aortic Valve With Raphe Formation

作者：Lin Ying, Qifan Yang, Xiaoping Lin, Xianbao Liu, Yi Qian, Dilin Xu, Naifang Cao, Ximeng Han, Yanqing Zhu, Wangxing Hu, Xiao‐Peng He, Zhengyang Yu, Xiangmin Kong, Lianlian Zhu, Zhiwei Zhong, Kai Liu, Bin Zhou, Yidong Wang, Jinrong Peng, Wei Zhu, Jianan Wang · 发表于：Circulation · 年份：2023 · DOI：10.1161/circulationaha.123.065458 · 被引用次数：18 · 研究领域：Congenital heart defects research、Cell Adhesion Molecules Research、Connective tissue disorders research

BACKGROUND: A better understanding of the molecular mechanism of aortic valve development and bicuspid aortic valve (BAV) formation would significantly improve and optimize the therapeutic strategy for BAV treatment. Over the past decade, the genes involved in aortic valve development and BAV formation have been increasingly recognized. On the other hand, ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) gene family members have been reported to be able to modulate cardiovascular development and diseases. The present study aimed to further investigate the roles of ADAMTS family members in aortic valve development and BAV formation. METHODS: Morpholino-based ADAMTS family gene-targeted screening for zebrafish heart outflow tract phenotypes combined with DNA sequencing in a 304 cohort BAV patient registry study was initially carried out to identify potentially related genes. Both ADAMTS gene-specific fluorescence in situ hybridization assay and genetic tracing experiments were performed to evaluate the expression pattern in the aortic valve. Accordingly, related genetic mouse models (both knockout and knockin) were generated using the CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat–associated 9) method to further study the roles of ADAMTS family genes. The lineage-tracing technique was used again to evaluate how the cellular activity of specific progenitor cells was regulated b...