先天性脊柱畸形 z-bio 2025-02-14 305

　　Figure: Schematic diagram of the mechanism by which the structure and variation of the SOX9 gene TAM affect axial bone homeostasis

　　Under the support of National Natural Science Foundation of China projects (approval numbers: 82102522, 82072391, 82172382), Professor Wu Nan and Professor Jian Guo's team from Peking Union Medical College Hospital, in collaboration with Professor Ryan S. Gray's team from the University of Texas at Austin and Professor Liu Zhaoyang's team from the University of Southern California, have made progress in the study of the pathogenesis of congenital spinal deformities. The research findings, titled "Variants in the SOX9 transactivation middle domain induced axial skeletal dysplasia and scoliosis," were published online on January 24, 2025 in the Proceedings of the National Academy of Sciences (PNAS) journal. Paper link: https://www.pnas.org/doi/10.1073/pnas.2313978121 .

　　Congenital vertebral malformation (CVM) refers to the congenital formation or segmentation disorders of the vertebral body. As the patient ages, progressive spinal deformities and impaired cardiopulmonary function may occur, which can have serious physiological and psychological effects on the patient. SOX9 is an important transcription factor that regulates cartilage development and is crucial for the development and homeostasis of axial bone. Therefore, in-depth research on the association between CVM and SOX9 gene mutations will help understand the pathogenesis of CVM and enable early diagnosis and treatment.

　　The collaborative research team identified 4 missense mutations in SOX9 through whole exome sequencing analysis of 424 CVM patients, including 1 located in the transactivation middle domain (TAM). By constructing TAM point mutant mice (Asp272del), it was found that TAM mutations lead to mild axial bone dysplasia and decreased local SOX9 expression after delivery. The cooperative research team studied the pathogenic mechanism of TAM mutation through in vitro gel migration and luciferase reporter gene experiment respectively, proving that TAM mutation will not affect the DNA binding ability and transcriptional activity of SOX9; Through in vitro cell culture, it was found that TAM mutations can reduce the protein stability of SOX9 and affect in vitro cartilage formation; Further sequencing results indicate that TAM is crucial for maintaining the expression of extracellular matrix components required for SOX9 and its downstream annulus fibrosus homeostasis. Through X-ray and slice staining analysis, it was found that 6-month-old point mutant mice exhibited delayed scoliosis, rib deformities, and intervertebral disc degeneration. The expression of cartilage hypertrophy markers such as endplate COLX, IHH, and RUNX2 increased, suggesting that TAM point mutations may disrupt SOX9's regulation of cartilage maturation by reducing SOX9 stability, leading to spinal deformities and degeneration (Figure).

　　This study reported pathogenic mutations of SOX9 in a cohort of congenital spinal deformities and investigated the mechanism of mild axial dysplasia caused by TAM mutations in SOX9, providing a theoretical basis for early diagnosis and genetic counseling of spinal deformities.