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 8.855
Human and Animal Cells ATDC5(RCB0565)