TY - JOUR
T1 - Loss of DDRGK1 modulates SOX9 ubiquitination in spondyloepimetaphyseal dysplasia
AU - Egunsola, Adetutu T.
AU - Bae, Yangjin
AU - Jiang, Ming Ming
AU - Liu, David S.
AU - Chen-Evenson, Yuqing
AU - Bertin, Terry
AU - Chen, Shan
AU - Lu, James T.
AU - Nevarez, Lisette
AU - Magal, Nurit
AU - Raas-Rothschild, Annick
AU - Swindell, Eric C.
AU - Cohn, Daniel H.
AU - Gibbs, Richard A.
AU - Campeau, Philippe M.
AU - Shohat, Mordechai
AU - Lee, Brendan H.
N1 - Funding Information:
Acknowledgments This work was supported by the Baylor College of Medicine Intellectual and Developmental Disabilities Research Center (HD024064) from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the Baylor College of Medicine Advanced Technology Cores with funding from the NIH (AI036211, CA125123, and RR024574), the Rolanette and Berdon Lawrence Bone Disease Program of Texas, and the Baylor College of Medicne Center for Skeletal Medicine and Biology. It was also supported by NIH grant R01AR062651 and the Adler chair for Pediatric Cardiology, Tel Aviv University.
PY - 2017/4/3
Y1 - 2017/4/3
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85018711896&partnerID=8YFLogxK
U2 - 10.1172/JCI90193
DO - 10.1172/JCI90193
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C2 - 28263186
AN - SCOPUS:85018711896
SN - 0021-9738
VL - 127
SP - 1475
EP - 1484
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 4
ER -