HGNC Approved Gene Symbol: OPLL
DO: 0060887;
Ossification of the posterior longitudinal ligament of the spine (OPLL) is a common degenerative spinal disorder that causes severe neurologic dysfunction in middle-aged and elderly populations. This ectopic ossification results in compression of the spinal cord and nerve root by the ossified ligament. Histologic studies of OPLL suggest that OPLL develops through a process of endochondral ossification (summary by Nakajima et al., 2016).
OPLL can cause spinal-cord compression (Ono et al., 1977; Tsuyama, 1984). Patients with OPLL frequently present with a severe myelopathy that can lead to tetraparesis. X-ray examination detects OPLL in 0.7 to 2.0% of adult outpatients with cervical disorders (Firooznia et al., 1982); the observed incidence increases to 3.7% in patients over 50 years of age (Ohtsuka et al., 1987).
From a study of 55 Chinese patients with OPLL, Chen et al. (2016) noted that although the continuous and segmental subtypes had previously been found to be predominant, radiologic analysis in this cohort revealed the most predominant subtype to be local OPLL, present in 23 patients (41.8%), whereas the continuous subtype was present in only 5 (9.1%). In addition, the mixed subtype was present in 15 patients (25.5%) and the segmental subtype in 13 (23.6%).
Familial aggregation of OPLL was observed by Terayama (1989), who identified OPLL in 192 sibs of 636 patients.
Koga et al. (1998) stated that OPLL is recognized as a common disorder among Japanese and throughout Asia. Estimates of its prevalence are in the range of 1.9 to 4.3%.
Based on the finding of a mutation in the Npps gene (ENPP1; 173335) in the ttw mouse (see ANIMAL MODEL) by Okawa et al. (1998), Nakamura et al. (1999) examined genetic variations in the NPPS gene, which maps to chromosome 6q22-q23, in patients with OPLL. A total of 323 OPLL patients were screened by means of PCR/SSCP analysis covering all the exons and their surrounding introns, plus about 1.5 kb of the promoter region. They identified 10 nucleotide variations in the ENPP1 gene; 5 of the alterations caused amino acid substitutions, and 2 of them were found specifically in OPLL patients. Subsequently, Nakamura et al. (1999) performed an association study using these variations and found a significant association of OPLL with 1 allele: a deletion of T at a position 11 nucleotides upstream from the splice acceptor site of intron 20 (IVS20-11delT; 173335.0001). The proportion of individuals having this deletion was significantly higher (p = 0.0029) in OPLL patients than in controls, indicating that those who have this variation may be more susceptible to the abnormal ossification of the spinal ligaments.
Koga et al. (1998) identified a predisposing locus for OPLL on 6p, close to the HLA complex. The evidence for this localization was provided by a genetic linkage study of 91 affected sib pairs in 53 Japanese families. Significant evidence of linkage was found with D6S276, a marker lying close to the HLA complex (p = 0.000006). A candidate gene in this region, COL11A2 (120290), located at 6p21.3, was analyzed for the presence of molecular variants in affected probands. Of 19 distinct variants identified, 4 showed strong statistical associations with OPLL.
Among Japanese, in whom OPLL is a leading cause of myelopathy, causing ectopic bone formation in the paravertebral ligament, Maeda et al. (2001) found a male-specific association of a COL11A2 haplotype with OPLL.
Tanaka et al. (2003) performed a genomewide linkage study of 142 affected sib pairs to identify genetic loci related to OPLL. The best evidence of linkage was detected near marker D21S1903 on 21q22.3; the linkage region was therefore extensively investigated for linkage disequilibrium with SNPs covering 20 Mb. Haplotype analysis with 3 SNPs in the COL6A1 gene (120220) gave a single-point p value of 0.0000007.
In a case-control study of 711 Japanese individuals with OPLL and 896 controls, Horikoshi et al. (2006) found an association between an intronic SNP (rs2268624) in the TGFB3 gene (190230), which maps to chromosome 14q24, and OPLL. Previously reported associations of COL11A2, ENPP1, and TGFB1 (190180) with OPLL were not reproduced.
Nakajima et al. (2014) performed a genomewide association study in 1,130 Japanese patients with OPLL and 7,135 controls, followed by a replication study involving an independent set of 548 Japanese patients with OPLL and 6,469 controls. They identified 6 susceptibility loci for OPLL: 20p12.3 (rs2423294; p = 1.10 x 10(-13)); 8q23.1 (rs374810; p = 1.88 x 10(-13)); 12p11.22 (rs1979679; p = 4.34 x 10(-12)); 12p12.2 (rs11045000; p = 2.95 x 10(-11)); 8q23.3 (rs13279799; p = 1.28 x 10(-10)); and 6p21.1 (rs927485; p = 9.40 x 10(-9)).
Associations Pending Confirmation
In 55 Chinese patients with OPLL, Chen et al. (2016) performed targeted exome sequencing of 11 OPLL-associated genes and identified potentially pathogenic missense variants in 4 genes, including 3 in COL6A1, 2 in COL11A2, 2 in FGFR1 (136350), and 1 in BMP2 (112261).
Nakajima et al. (2016) studied the most significant OPLL-associated SNP at chromosome 8q23.1, rs374810, located in an apparent promoter region 116 bp upstream of the transcription start site of the RSPO2 gene (610575). Experiments in ATDC5 cells, a model for endochondral ossification, demonstrated that RSPO2 regulates early chondrocyte differentiation through canonical Wnt signaling. Analysis of cultured fibroblast mRNA from 61 normal controls showed that individuals carrying the risk allele 'C' (TC and CC genotypes) had significantly lower RSPO2 expression than those with a TT genotype. Nakajima et al. (2016) concluded that RSPO2 is a susceptibility gene for OPLL.
Twy ('tiptoe' walking Yoshimura) mouse is a naturally occurring mutant that exhibits ossification of the spinal ligaments similar to OPLL (Yamazaki et al., 1991). The trait is inherited as an autosomal recessive with almost complete penetrance. Ossification of the spinal ligaments occurs spontaneously at about 6 weeks of age and progresses relentlessly, resulting in severe motor paresis of limbs. The changes in the spinal ligaments closely resemble those of human OPLL. In the study of F2 progeny, Okawa et al. (1998) observed that heterotopic ossification occurs not only in the spinal ligaments but also in the joint capsules, tendon enthesis, chondral tissues, and peripheral ligaments. Okawa et al. (1998) mapped the twy gene within an interval of approximately 2.6 cM in the proximal portion of mouse chromosome 10, by a genome screen using microsatellite markers.
To elucidate the genetic basis of OPLL, studies were undertaken of the ttw ('tiptoe walking'; previously designated twy) mouse, a naturally occurring mutant that exhibits ossification of the spinal ligaments very similar to human OPLL. Using a positional candidate-gene approach, Okawa et al. (1998) determined that the ttw phenotype is caused by a nonsense mutation (gly568 to ter) in the Npps gene which encodes nucleotide pyrophosphatase (NPPS, or ENPP1; 173335). This enzyme regulates soft-tissue calcification and bone mineralization by producing inorganic pyrophosphate, a major inhibitor of calcification. The accelerated bone formation characteristic of ttw mice was thought to result from dysfunction of Npps caused by predicted truncation of the gene product, resulting in the loss of more than one-third of the native protein. The results provided novel insights into the mechanism of ectopic ossification and the etiology of human OPLL.
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