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

Loss of DDRGK1 modulates SOX9 ubiquitination in spondyloepimetaphyseal dysplasia

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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Figure 1

Homozygous DDRGK1 loss-of-function mutation identified in Iraqi Jewish families with Shohat-type SEMD.

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Homozygous DDRGK1 loss-of-function mutation identified in Iraqi Jewish f...
(A) Pedigree of family 1. M represents mutant allele. Asterisks indicate individuals who were selected for WES. (B) Radiographs from family 1 reveal platyspondyly and hypomineralized epiphyses and metaphyses in patients 1 and 2, respectively. (C and D) Pedigrees of families 2, 3, and 4. (E) Radiographs show severe scoliosis, vertebral compression factures, platyspondyly, broaden hypomineralized metaphyses, and smaller than average hypomineralized epiphyses in patient 5 from family 4. (F) Schematic of the c.408+1G>A mutation in the DDRGK1 gene. (G) Western analysis of whole cell lysates reveals absence of DDRGK1 expression in patient LCLs.