Research Papers:

Knock-in human GDF5 proregion L373R mutation as a mouse model for proximal symphalangism

Xinxin Zhang, Xuesha Xing, Xing Liu, Yu Hu, Shengqiang Qu, Heyi Wang and Yang Luo _

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Oncotarget. 2017; 8:113966-113976. https://doi.org/10.18632/oncotarget.23047

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Xinxin Zhang1,*, Xuesha Xing1,*, Xing Liu1, Yu Hu1, Shengqiang Qu1, Heyi Wang1 and Yang Luo1

1The Research Center for Medical Genomics, Key Laboratory of Cell Biology, Ministry of Public Health, Key Laboratory of Medical Cell Biology, Ministry of Education, College of Basic Medical Science, China Medical University, Shenyang, Liaoning, China

*These authors have contributed equally to this work

Correspondence to:

Yang Luo, email: [email protected]

Keywords: GDF5; SYM1; proregion; knock-in; gain-of-function

Received: July 28, 2017    Accepted: September 20, 2017    Published: December 08, 2017


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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