Knock-in human GDF5 proregion L373R mutation as a mouse model for proximal symphalangism.
Knock-in human GDF5 proregion L373R mutation as a mouse model for proximal symphalangism.
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敲入人 GDF5 前区 L373R 突变作为近端交感神经的小鼠模型
DOI：
10.18632/oncotarget.23047
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发表时间：
2017-12-26
期刊：
影响因子：
--
通讯作者：
Luo Y
中科院分区：
文献类型：
--
作者：
Zhang X;Xing X;Liu X;Hu Y;Qu S;Wang H;Luo Y
近端指骨畸形（SYM1）是一种常染色体显性遗传疾病，主要特征是手和足的近端指骨的骨融合。 GDF5 和 NOG 被确定与 SYM1 相关。我们之前曾报道过中国 SYM1 家系中存在 GDF5 前区的 p.Leu373Arg 突变。在这里，我们研究了 GDF-L373R 突变的影响。该变异导致 ATDC5 细胞中 GDF5 的蛋白水解效率增加。该变异还导致 SMAD1/5/8 磷酸化上调，并增加靶基因 SMURF1 以及与软骨病相关的因子 COL2A1 和 SOX9 的表达。此外，我们通过制作 Gdf5L367R（人类 L373R 的直系同源位置）敲入小鼠，开发了人类相关的 SYM1 小鼠模型。 Gdf5L367R/+ 和 Gdf5L367R/L367R 小鼠表现出近端指骨关节僵硬和粘连，这与 SYM1 完全一致。还证实Gdf5L367R/+和Gdf5L367R/L367R小鼠的关节形成和发育异常，包括在胚胎发育过程中未能发育初级骨化中心和肥大软骨细胞。该敲入小鼠模型提供了评估 SYM1 发病机制和 GDF5 前区功能的工具。
Proximal symphalangism (SYM1) is an autosomal dominant disorder, mainly characterized by bony fusions of the proximal phalanges of the hands and feet. GDF5 and NOG were identified to be responsible for SYM1. We have previously reported on a p.Leu373Arg mutation in the GDF5 proregion present in a Chinese family with SYM1. Here, we investigated the effects of the GDF-L373R mutation. The variant caused proteolysis efficiency of GDF5 increased in ATDC5 cells. The variant also caused upregulation of SMAD1/5/8 phosphorylation and increased expression of target genes SMURF1, along with COL2A1 and SOX9 which are factors associated with chondrosis. Furthermore, we developed a human-relevant SYM1 mouse model by making a Gdf5L367R (the orthologous position for L373R in humans) knock-in mouse. Gdf5L367R/+ and Gdf5L367R/L367R mice displayed stiffness and adhesions across the proximal phalanx joint which were in complete accord with SYM1. It was also confirmed the joint formation and development was abnormal in Gdf5L367R/+ and Gdf5L367R/L367R mice, including the failure to develop the primary ossification center and be hypertrophic chondrocytes during embryonic development. This knock-in mouse model offers a tool for assessing the pathogenesis of SYM1 and the function of the GDF5 proregion.
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