| RRC ID |
51780
|
| Author |
Nakajima M, Kou I, Ohashi H, Genetic Study Group of the Investigation Committee on the Ossification of Spinal Ligaments, Ikegawa S.
|
| Title |
Identification and Functional Characterization of RSPO2 as a Susceptibility Gene for Ossification of the Posterior Longitudinal Ligament of the Spine.
|
| Journal |
Am J Hum Genet
|
| Abstract |
Ossification of the posterior longitudinal ligament of the spine (OPLL) is a common spinal disorder that results from ectopic ossification of the posterior longitudinal ligament and causes intractable myelopathy and radiculopathy. In a previous genome-wide association study (GWAS), we found six loci associated with OPLL; however, susceptibility genes in these loci have not been identified yet. Here, we examined one of the GWAS loci and identified RSPO2 (encoding R-spondin 2) as a susceptibility gene for OPLL. R-spondin 2 is a secreted agonist of canonical Wnt-β-catenin signaling. RSPO2 was decreased in the early stage of chondrocyte differentiation. R-spondin 2 inhibited expression of genes encoding early chondrocyte differentiation markers by activating Wnt-β-catenin signaling. rs374810, the most significantly associated SNP in the GWAS locus in chromosomal region 8q23.1 was located in the chondrocyte promoter region of RSPO2. A transcription factor, CCAAT-enhancer-binding protein β (C/EBPβ), specifically bound to the RSPO2 core promoter region containing rs374810 and increased RSPO2 expression. The risk allele of rs374810 affected the binding of the promoter with C/EBPβ and decreased the RSPO2 transcription in vitro and in vivo. Our genetic and functional data indicate that RSPO2 is a susceptibility gene for OPLL.
|
| Volume |
99(1)
|
| Pages |
202-7
|
| Published |
2016-7-7
|
| DOI |
10.1016/j.ajhg.2016.05.018
|
| PII |
S0002-9297(16)30153-7
|
| PMID |
27374772
|
| PMC |
PMC5005442
|
| MeSH |
Cell Line
Genetic Predisposition to Disease / genetics*
Humans
Intercellular Signaling Peptides and Proteins / genetics*
Ossification of Posterior Longitudinal Ligament / genetics*
Polymorphism, Single Nucleotide / genetics
Wnt Signaling Pathway
beta Catenin / metabolism
|
| IF |
10.502
|
| Times Cited |
14
|
| Resource |
| Human and Animal Cells |
ATDC5(RCB0565) |
