A rare variant in the osteoarthritis-associated locus GDF5 is functional and reveals a site that can be manipulated to modulate GDF5 expression
Open Access
- 29 August 2012
- journal article
- research article
- Published by Springer Science and Business Media LLC in European Journal of Human Genetics
- Vol. 21 (5), 517-521
- https://doi.org/10.1038/ejhg.2012.197
Abstract
Osteoarthritis (OA) is a polygenic disease characterized by cartilage loss, with the single-nucleotide polymorphism (SNP) rs143383 (C/T) influencing OA susceptibility across a range of ethnic groups. The SNP resides within the 5′-UTR of the growth and differentiation factor 5 gene (GDF5), with the OA-associated T-allele mediating reduced GDF5 expression. As GDF5 codes for a cartilage anabolic protein, this reduced expression may explain why the T-allele of rs143383 is an OA risk factor. Our deep sequencing of GDF5 identified a C/A transversion located −41 bp relative to the gene’s transcription start site. This promoter variant is predicted to affect transcription factor binding and it may therefore highlight a regulatory site that could be exploited to manipulate GDF5 expression and alleviate the detrimental effect mediated by the T-allele of rs143383. Here, we describe our functional assessment of the −41 bp variant. Using reporter constructs we demonstrated that the transversion leads to increased gene expression to such a degree that the A-allele is able to compensate for the reduced expression mediated by the T-allele of rs143383. Using electrophoretic mobility shift assays we identified YY1 as a trans-acting factor that differentially binds to the alleles of the −41 bp variant, with more avid binding to allele A. Knockdown of YY1 led to a significant reduction in GDF5 expression, supporting YY1 as a GDF5 activator. In conclusion, we demonstrated that the −41 bp variant is functional and we have identified a regulatory region of GDF5 that can be exploited to overcome the OA genetic deficit mediated by the T-allele of rs143383.Keywords
This publication has 20 references indexed in Scilit:
- GDF5 deficiency in mice is associated with instability-driven joint damage, gait and subchondral bone changesAnnals Of The Rheumatic Diseases, 2010
- Etiopathogenesis of OsteoarthritisRheumatic Disease Clinics of North America, 2008
- A meta-analysis of European and Asian cohorts reveals a global role of a functional SNP in the 5' UTR of GDF5 with osteoarthritis susceptibilityHuman Molecular Genetics, 2008
- An SNP in the 5′-UTR of GDF5 is associated with osteoarthritis susceptibility in Europeans and with in vivo differences in allelic expression in articular cartilageHuman Molecular Genetics, 2007
- A functional polymorphism in the 5′ UTR of GDF5 is associated with susceptibility to osteoarthritisNature Genetics, 2007
- Multiple Effects of GDF-5 Deficiency on Skeletal Tissues: Implications for Therapeutic BioengineeringAnnals of Biomedical Engineering, 2004
- Multiple joint and skeletal patterning defects caused by single and double mutations in the mouse Gdf6 and Gdf5 genesDevelopmental Biology, 2003
- Disruption of human limb morphogenesis by a dominant negative mutation in CDMP1Nature Genetics, 1997
- Mutations in CDMP1 cause autosomal dominant brachydactyly type CNature Genetics, 1997
- A human chondrodysplasia due to a mutation in a TGF-β superfamily memberNature Genetics, 1996