单位：[1]Department of Otolaryngology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China,[2]Department of Otolaryngology, China-Japan Friendship Hospital, Beijing, China,[3]Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China,[4]School of Medicine, Tsinghua University, Beijing, China,[5]Department of Cardiology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China,[6]Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China,[7]Department of Otolaryngology, The Ohio State University, Columbus, OH, United States,[8]Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, College of Life Sciences, Peking University, Beijing, China,[9]Department of Medical Genetics and National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China,[10]Department of Otolaryngology Head and Neck Surgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China首都医科大学附属天坛医院
Background Hemifacial microsomia (HFM) is a type of rare congenital syndrome caused by developmental disorders of the first and second pharyngeal arches that occurs in one out of 5,600 live births. There are significant gaps in our knowledge of the pathogenic genes underlying this syndrome. Methods Whole exome sequencing (WES) was performed on five patients, one asymptomatic carrier, and two marry-in members of a five-generation pedigree. Structure of WARP (product ofVWA1) was predicted using the Phyre2 web portal.In situhybridization andvwa1-knockdown/knockout studies in zebrafish using morpholino and CRISPR/Cas9 techniques were performed. Cartilage staining and immunofluorescence were carried out. Results Through WES and a set of filtration, we identified a c.G905A:p.R302Q point mutation in a novel candidate pathogenic gene,VWA1. The Phyre2 web portal predicted alterations in secondary and tertiary structures of WARP, indicating changes in its function as well. Predictions of protein-to-protein interactions in five pathways related to craniofacial development revealed possible interactions with four proteins in the FGF pathway. Knockdown/knockout studies of the zebrafish revealed deformities of pharyngeal cartilage. A decrease of the proliferation of cranial neural crest cells (CNCCs) and alteration of the structure of pharyngeal chondrocytes were observed in the morphants as well. Conclusion Our data suggest that a mutation inVWA1is functionally linked to HFM through suppression of CNCC proliferation and disruption of the organization of pharyngeal chondrocytes.
基金：
General Programs of National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81974143]; National Key Research and Development Program of China [2016YFC0901500]
第一作者单位：[1]Department of Otolaryngology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China,[2]Department of Otolaryngology, China-Japan Friendship Hospital, Beijing, China,
共同第一作者：
通讯作者：
推荐引用方式(GB/T 7714)：
Yibei Wang,Lu Ping,Xiaodong Luan,et al.A Mutation inVWA1, Encoding von Willebrand Factor A Domain-Containing Protein 1, Is Associated With Hemifacial Microsomia[J].FRONTIERS in CELL and DEVELOPMENTAL BIOLOGY.2020,8:doi:10.3389/fcell.2020.571004.
APA：
Yibei Wang,Lu Ping,Xiaodong Luan,Yushan Chen,Xinmiao Fan...&Xiaowei Chen.(2020).A Mutation inVWA1, Encoding von Willebrand Factor A Domain-Containing Protein 1, Is Associated With Hemifacial Microsomia.FRONTIERS in CELL and DEVELOPMENTAL BIOLOGY,8,
MLA：
Yibei Wang,et al."A Mutation inVWA1, Encoding von Willebrand Factor A Domain-Containing Protein 1, Is Associated With Hemifacial Microsomia".FRONTIERS in CELL and DEVELOPMENTAL BIOLOGY 8.(2020)
