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Citations to this article

Loss of DDRGK1 modulates SOX9 ubiquitination in spondyloepimetaphyseal dysplasia
Adetutu T. Egunsola, … , Mordechai Shohat, Brendan H. Lee
Adetutu T. Egunsola, … , Mordechai Shohat, Brendan H. Lee
Published March 6, 2017
Citation Information: J Clin Invest. 2017;127(4):1475-1484. https://doi.org/10.1172/JCI90193.
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Research Article Bone biology Genetics Article has an altmetric score of 6

Loss of DDRGK1 modulates SOX9 ubiquitination in spondyloepimetaphyseal dysplasia

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Abstract

Shohat-type spondyloepimetaphyseal dysplasia (SEMD) is a skeletal dysplasia that affects cartilage development. Similar skeletal disorders, such as spondyloepiphyseal dysplasias, are linked to mutations in type II collagen (COL2A1), but the causative gene in SEMD is not known. Here, we have performed whole-exome sequencing to identify a recurrent homozygous c.408+1G>A donor splice site loss-of-function mutation in DDRGK domain containing 1 (DDRGK1) in 4 families affected by SEMD. In zebrafish, ddrgk1 deficiency disrupted craniofacial cartilage development and led to decreased levels of the chondrogenic master transcription factor sox9 and its downstream target, col2a1. Overexpression of sox9 rescued the zebrafish chondrogenic and craniofacial phenotype generated by ddrgk1 knockdown, thus identifying DDRGK1 as a regulator of SOX9. Consistent with these results, Ddrgk1–/– mice displayed delayed limb bud chondrogenic condensation, decreased SOX9 protein expression and Col2a1 transcript levels, and increased apoptosis. Furthermore, we determined that DDRGK1 can directly bind to SOX9 to inhibit its ubiquitination and proteasomal degradation. Taken together, these data indicate that loss of DDRGK1 decreases SOX9 expression and causes a human skeletal dysplasia, identifying a mechanism that regulates chondrogenesis via modulation of SOX9 ubiquitination.

Authors

Adetutu T. Egunsola, Yangjin Bae, Ming-Ming Jiang, David S. Liu, Yuqing Chen-Evenson, Terry Bertin, Shan Chen, James T. Lu, Lisette Nevarez, Nurit Magal, Annick Raas-Rothschild, Eric C. Swindell, Daniel H. Cohn, Richard A. Gibbs, Philippe M. Campeau, Mordechai Shohat, Brendan H. Lee

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Total citations by year

Year: 2025 2024 2023 2022 2021 2020 2019 Total
Citations: 4 5 10 6 5 1 7 38
Citation information
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Citations to this article in year 2021 (5)

Title and authors Publication Year
Targeting chondrocytes for arresting bony fusion in ankylosing spondylitis
F Shao, Q Liu, Y Zhu, Z Fan, W Chen, S Liu, X Li, W Guo, GS Feng, H Yu, Q Xu, Y Sun
Nature Communications 2021
Zebrafish Models for Human Skeletal Disorders
M Marí-Beffa, AB Mesa-Román, I Duran
Frontiers in Genetics 2021
Enzymatic Machinery of Ubiquitin and Ubiquitin-Like Modification Systems in Chondrocyte Homeostasis and Osteoarthritis
Y Liu, V Molchanov, T Yang
Current Rheumatology Reports 2021
DDRGK1, a crucial player of ufmylation system, is indispensable for autophagic degradation by regulating lysosomal function
Y Cao, R Li, M Shen, C Li, Y Zou, Q Jiang, S Liu, C Lu, H Li, H Liu, Y Cai
Cell Death and Disease 2021
p53-mediated G1 arrest requires the induction of both p21 and Killin in human colon cancer cells
D Luo, C Yu, J Yu, C Su, S Li, P Liang
Cell cycle (Georgetown, Tex.) 2021

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