Variants in the SOX9 transactivation middle domain induce axial skeleton dysplasia and scoliosis
Abstract
SOX9 is a crucial transcriptional regulator of cartilage development and homeostasis. Dysregulation of SOX9 is associated with a wide spectrum of skeletal disorders, including campomelic dysplasia, acampomelic campomelic dysplasia, and scoliosis. Yet how SOX9 variants contribute to the spectrum of axial skeletal disorders is not well understood. Here, we report four pathogenic variants of SOX9 identified in a cohort of patients with congenital vertebral malformations. We report a pathogenic missense variant in the transactivation middle (TAM) domain of SOX9 associated with mild skeletal dysplasia and scoliosis. We isolated a Sox9 mutant mouse with an in-frame microdeletion in the TAM domain ( Sox9 Asp272del ), which exhibits skeletal dysplasia including kinked tails, rib cage anomalies, and scoliosis in homozygous mutants. We find that both the human missense and the mouse microdeletion mutations resulted in reduced SOX9 protein stability in cell culture, while Sox9 Asp272del mutant mice show decreased SOX9 expression in the growth plate and annulus fibrosus tissues of the spine. This reduction in SOX9 expression was correlated with the reduction of extracellular matrix components, such as tenascin-X and the Adhesion G-protein coupled receptor ADGRG6. In summary, our work identified and modeled a pathologic variant of SOX9 within the TAM domain and demonstrated its importance for SOX9 protein stability. Our work demonstrates that SOX9 stability is important for the regulation of ADGRG6 expression, which is a known regulator of postnatal spine homeostasis, underscoring the essential role of SOX9 dosage in a spectrum of axial skeleton dysplasia in humans.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (68)
Zhaoyang Liu
State Key Laboratory of Supramolecular Structure and Materials
Valeria Aceves
Department of Nutritional Sciences, Dell Pediatric Research Institute, The University of Texas at Austin, Dell Medical School
Hong Colleen Feng
Center for Craniofacial Molecular Biology, Herman Ostrow School of Dentistry, University of Southern California
Fangzhou Bian
Center for Craniofacial Molecular Biology, Herman Ostrow School of Dentistry, University of Southern California
Jingyu He
Center for Craniofacial Molecular Biology, Herman Ostrow School of Dentistry, University of Southern California
Christina J. Song
Department of Nutritional Sciences, Dell Pediatric Research Institute, The University of Texas at Austin, Dell Medical School
Benjamin Troutwine
Department of Nutritional Sciences, Dell Pediatric Research Institute, The University of Texas at Austin, Dell Medical School
Samuel Ma
Department of Nutritional Sciences, Dell Pediatric Research Institute, The University of Texas at Austin, Dell Medical School
Suomao Yuan
Department of Orthopedic Surgery, Qilu Hospital of Shandong University
Xiaoxin Li
Beijing Key Laboratory of Big Data Innovation and Application for Skeletal Health Medical Care
Xinyu Liu
Terry Jianguo Zhang
Department of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College
Ryan S. Gray
Department of Nutritional Sciences, Dell Pediatric Research Institute, The University of Texas at Austin, Dell Medical School
Guixing Qiu
Department of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College
Nan Wu
Jianguo Zhang
Zhihong Wu
Beijing Key Laboratory of Big Data Innovation and Application for Skeletal Health Medical Care
Shengru Wang
Department of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College
Sen Liu
Ziquan Li
Yang Yang
Zhengye Zhao
Guilin Chen
Guozhuang Li
Yuanpeng Zhu
Jihao Cai
Di Liu
Kexin Xu
Jianle Yang
Aoran Maheshati
Qing Li
Jingyi Xie
Xiangjie Yin
Jialuo Han
Cheng Qiu
Department of Orthopedic Surgery, Qilu Hospital of Shandong University
Ze Liu
Shufang Zhu
Junjie Xia
Jie Wang
State Key Laboratory of Molecular Oncology, Beijing Key Laboratory, CAMS Key Laboratory of Translational Research on Lung Cancer, Department of Medical Oncology Cancer Hospital, Chinese Academy of Medical Sciences Beijing China
Zihua Li
Luyuan Qiu
Ning Zhang
Zhifa Zheng
Kun Fang
Xiangyu Nie
Xi Cheng
State Key Laboratory of Catalysis, Dalian Institute of Chemical Physics
Wen Wen
Xinyu Yang
Yuanqiang Zhang
Lian Liu
Department of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College
Lianlei Wang
Department of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College
Na Chen
Jiachen Lin
Mao Lin
Lina Zhao
Beijing Key Laboratory of Big Data Innovation and Application for Skeletal Health Medical Care
Fei Liu
Yuchen Niu
Beijing Key Laboratory of Big Data Innovation and Application for Skeletal Health Medical Care
Qing Liu
Department of Otolaryngology Head and Neck Surgery, Jiangsu Provincial Key Medical Discipline (Laboratory), Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University
Guangxi Gao
Yueyan Bai
Sen Zhao
Yongyu Ye
Hengqiang Zhao
Zefu Chen
Jiaqi Liu
Zihui Yan
Chenxi Yu
Jiashen Shao