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.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5373861 | PMC |
| http://dx.doi.org/10.1172/JCI90193 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Protein UFMylation regulates early events during ribosomal DNA-damage response.
Cell Rep
September 2024
Institut de recherches cliniques de Montréal, Center for Genetic and Neurological Diseases, 110 avenue des Pins Ouest, Montréal, QC H2W 1R7, Canada; Division of Experimental Medicine, Faculty of Medicine, McGill University, Montréal, QC H4A 3J1, Canada; Département de biochimie et médicine moléculaire, Faculté de Médicine, Université de Montréal, Montréal, QC H3C 3J7, Canada. Electronic address:
Article Synopsis
- * When this DNA is broken, a process called UFMylation helps fix it by changing how certain proteins work and moving them to help repair the damage.
- * If a protein called UFL1 isn't working properly, it causes problems in repairing the rDNA and can lead to less effective cell function.
Loss of DDRGK1 impairs IRE1α UFMylation in spondyloepiphyseal dysplasia.
Int J Biol Sci
October 2023
Shanghai Key Laboratory of Orthopedic Implants, Department of Orthopedics, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Spondyloepiphyseal dysplasia (SEMD) is a rare disease in which cartilage growth is disrupted, and the DDRGK1 mutation is one of the causative genes. In our study, we established , -ERT Cre mice, which showed a thickened hypertrophic zone (HZ) in the growth plate, simulating the previous reported SEMD pathology . Instead of the classical modulation mechanism towards SOX9, our further mechanism study found that DDRGK1 stabilizes the stress sensor endoplasmic reticulum-to-nucleus signaling 1 (IRE1α) to maintain endoplasmic reticulum (ER) homoeostasis.
View Article and Find Full Text PDFA neuroprotective role of Ufmylation through Atg9 in the aging brain of Drosophila.
Cell Mol Life Sci
April 2023
College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China.
Ufmylation is a recently identified small ubiquitin-like modification, whose biological function and relevant cellular targets are poorly understood. Here we present evidence of a neuroprotective role for Ufmylation involving Autophagy-related gene 9 (Atg9) during Drosophila aging. The Ufm1 system ensures the health of aged neurons via Atg9 by coordinating autophagy and mTORC1, and maintaining mitochondrial homeostasis and JNK (c-Jun N-terminal kinase) activity.
View Article and Find Full Text PDFDDRGK1 is required for the proper development and maintenance of the growth plate cartilage.
Hum Mol Genet
August 2022
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Loss-of-function mutations in DDRGK1 have been shown to cause Shohat type spondyloepimetaphyseal dysplasia (SEMD). In zebrafish, loss of function of ddrgk1 leads to defects in early cartilage development. Ddrgk1-/- mice show delayed mesenchymal condensation in the limb buds and early embryonic lethality.
View Article and Find Full Text PDFDDRGK1, a crucial player of ufmylation system, is indispensable for autophagic degradation by regulating lysosomal function.
Cell Death Dis
April 2021
Department of Animal Genetics, Breeding and Reproduction, College of Animal Science and Technology, Nanjing Agricultural University, 210095, Nanjing, China.
DDRGK domain-containing protein 1 (DDRGK1) is an important component of the newly discovered ufmylation system and its absence has been reported to induce extensive endoplasmic reticulum (ER) stress. Recently, emerging evidence indicates that the ufmylation system is correlated with autophagy, although the exact mechanism remains largely unknown. To explore the regulation mechanism of DDRGK1 on autophagy, in this study, we established an immortalized mouse embryonic fibroblast (MEF) cell lines harvested from the DDRGK1:ROSA26-CreERT2 mice, in which DDRGK1 depletion can be induced by 4-hydroxytamoxifen (4-OHT) treatment.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!