Yu Tingting, Li Guoqiang, Wang Chen, Li Niu, Yao Ruen, Wang Jian
Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, China.
J Bone Miner Res. 2023 Apr;38(4):568-577. doi: 10.1002/jbmr.4785. Epub 2023 Feb 20.
Multiple synostoses syndromes (SYNS) are a group of rare genetic bone disorders characterized by multiple joint fusions. We previously reported an SYNS4-causing GDF6 c.1330 T > A (p.Tyr444Asn) mutation, which reduced Noggin-induced GDF6 inhibition and enhanced SMAD1/5/8 signaling. However, the mechanisms by which GDF6 gain-of-function mutation alters joint formation and the comprehensive molecular portraits of SYNS4 remain unclear. Herein, we introduce the p.Tyr443Asn (orthologous to the human GDF6 p.Tyr444Asn) mutation into the mouse Gdf6 locus and report the results of extensive phenotype analysis, joint development investigation, and transcriptome profiling of Gdf6 p.Tyr443Asn limb buds. Gdf6 p.Tyr443Asn knock-in mice recapitulated the morphological features of human SYNS4, showing joint fusion in the wrists, ankles, phalanges, and auditory ossicles. Analysis of mouse embryonic forelimbs demonstrated joint interzone formation defects and excess chondrogenesis in Gdf6 p.Tyr443Asn knock-in mice. Further, RNA sequencing of forelimb buds revealed enhanced bone formation and upregulated bone morphogenetic protein (BMP) signaling in mice carrying the Gdf6 p.Tyr443Asn mutation. Because tightly regulated BMP signaling is critical for skeletal development and joint morphogenesis, our study shows that enhancing GDF6 activity has a significant impact on both prenatal joint development and postnatal joint maintenance. © 2023 American Society for Bone and Mineral Research (ASBMR).
多发性关节融合综合征（SYNS）是一组罕见的遗传性骨骼疾病，其特征为多个关节融合。我们之前报道了一个导致SYNS4的GDF6基因c.1330 T > A（p.Tyr444Asn）突变，该突变减少了Noggin诱导的GDF6抑制作用并增强了SMAD1/5/8信号传导。然而，GDF6功能获得性突变改变关节形成的机制以及SYNS4的全面分子特征仍不清楚。在此，我们将p.Tyr443Asn（与人类GDF6 p.Tyr444Asn同源）突变引入小鼠Gdf6基因座，并报告了对Gdf6 p.Tyr443Asn肢体芽进行广泛表型分析、关节发育研究和转录组分析的结果。Gdf6 p.Tyr443Asn基因敲入小鼠重现了人类SYNS4的形态特征，表现为手腕、脚踝、指骨和听小骨的关节融合。对小鼠胚胎前肢的分析表明，Gdf6 p.Tyr443Asn基因敲入小鼠存在关节间区形成缺陷和软骨生成过多的情况。此外，前肢芽的RNA测序显示，携带Gdf6 p.Tyr443Asn突变的小鼠骨形成增强且骨形态发生蛋白（BMP）信号上调。由于严格调控的BMP信号对骨骼发育和关节形态发生至关重要，我们的研究表明增强GDF6活性对产前关节发育和产后关节维持均有显著影响。© 2023美国骨与矿物质研究学会（ASBMR）
