Human Retinoic X Receptor β: Complete Genomic Sequence and Mutation Search for Ossification of Posterior Longitudinal Ligament of the Spine

Numasawa, Takuya; Koga, Hiroaki; Ueyama, Kazumasa; Maeda, Shingo; Sakou, Takashi; Harata, Seiko; Leppert, M.; Inoue, Ituro

doi:10.1359/jbmr.1999.14.4.500

Cited by 58 publications

(21 citation statements)

References 24 publications

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“…Numasawa et al 22 examined the retinoic X receptor b (RXRβ) locus in 134 patients, as this gene was noted to be adjacent to COL11A2 in the murine and human genomes on chromosome 6 near the HLA locus. They discovered 3 variants, 2 of which showed a strong association with OPLL, suggesting that this gene and its location on chromosome 6 may be associated with the inheritance of OPLL.…”

Section: Large-scale Screening Studies For Candidate Genes In Opllmentioning

confidence: 99%

The genetics of ossification of the posterior longitudinal ligament

Stetler¹,

Marca²,

Park³

2011

FOC

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Object Ossification of the posterior longitudinal ligament (OPLL) is a pathological process of ectopic calcification with a preponderance for the cervical spine. Epidemiological and familial studies have both indicated predisposition; however, the genetic inheritance pattern and responsible genes for OPLL are still uncertain. The aim of this study was to evaluate and summarize the current understanding of the genetics underlying OPLL. Methods The authors reviewed epidemiological and genetic studies surrounding OPLL, with a particular focus on inheritance patterns and potential genes responsible for OPLL, using a PubMed database literature search. Results Despite an unclear inheritance pattern, there appears to be a strong familial link in patients with OPLL. Examination of these patterns using linkage analysis has shown multiple candidate genes that could be responsible for the inheritance of OPLL. Genes for collagen, nucleotide pyrophosphatase, transforming growth factors, and the vitamin D receptor have all been implicated. Additionally, multiple cytokines and growth factors, including bone morphogenetic proteins as well as other proteins and interleukins involved in bone development, have been shown to be abnormally expressed in patients with OPLL. In addition, multiple mechanical and metabolic factors such as hyperinsulinemia and obesity have been shown to be linked to OPLL. Conclusions Ossification of the posterior longitudinal ligament has a complex inheritance pattern. It does not appear that OPLL follows a simple, single-gene Mendelian inheritance pattern. Development of OPLL is more likely multifactorial in nature and develops in patients with a genetic predisposition from a variety of different mutations in various genes on various chromosomes. Additionally, environmental factors and interaction by other pathological disease processes, such as obesity and diabetes mellitus, may play a role in the development of OPLL in susceptible individuals.

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Section: Large-scale Screening Studies For Candidate Genes In Opllmentioning

confidence: 99%

The genetics of ossification of the posterior longitudinal ligament

Stetler¹,

Marca²,

Park³

2011

FOC

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“…Recent molecular genetic studies have identified several candidate genes that are differentially expressed in OPLL cells compared to normal ligament cells (15,16): reports suggest an increase in collagen, type VI, alpha 1 (Col6a1) (17,18); collagen type XI alpha 2 (Col11a2) (19,20); nucleotide pyrophosphatase (NPPS) (21 -24); leptin receptor (22); transforming growth factor-beta 1 (TGF-β1) (25 -27); promyelotic leukemia zinc finger (PLZF) (28,29); Tumor necrosis factor-alpha-stimulated gene 6 (TSG-6) (29); connective tissue growth factor (CTGF) (12); prostaglandin I 2 (PGI 2 ) (13) and endothelin-1 (30), amongst others. However, thus far, genetic factors have not been statistically linked to DISH or OPLL, most likely owing to the complexity of these diseases.…”

Section: Introductionmentioning

confidence: 99%

A Functional RNAi Screen for Runx2-Regulated Genes Associated With Ectopic Bone Formation in Human Spinal Ligaments

et al. 2008

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Abstract. Ossification of the posterior longitudinal ligament of the spine (OPLL) is characterized by ectopic ossification in the spinal ligaments, which enlarges with time and compresses the spinal cord, resulting in serious neurological symptoms. We previously reported that Runx2 expression was enhanced in spinal ligament cells from OPLL patients (OPLL cells). To clarify genes regulated by Runx2, Runx2 expression was first enhanced by culturing primary OPLL cells in osteogenic medium (OS induction) and then inhibited by siRNAs targeted to Runx2. DNA microarray demonstrated that in addition to chondrogenic factors such as connective tissue growth factor and cartilage oligomeric matrix protein, angiopoietin-1 was also significantly increased by OS induction and decreased by siRNAs for Runx2 in OPLL cells, suggesting that these genes are regulated by Runx2. However, these changes were not observed in non-OPLL control cells (from cervical spondylotic myelopathy patients). Furthermore, Runx2 was not decreased by siRNAs for angiopoietin-1. OS induction and RNAi inhibition of angiopoietin-1 expression was also observed in osteoblasts. Both siRNAs for Runx2 and angiopoietin-1 completely inhibited aggrecan-1 expression. These results suggest that angiopoietin-1 is downstream of Runx2 in both OPLL primary cells and osteoblasts. Angiopoietin-1 may play an important role in ectopic ossification.

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“…The two genes were screened for the molecular variations by single-strand conformation polymorphism (SSCP) analysis. No SSCP variant was detected in the coding or promoter regions of RXRB (Numasawa et al 1999). In COL11A2, we initially identified 19 distinct single nucleotide polymorphisms (SNPs) through extensive SSCP screening that included the promoter region, 66 exons, and intron 1 (Koga et al 1998).…”

Section: Introductionmentioning

confidence: 99%

Gender-specific haplotype association of collagen α2 (XI) gene in ossification of the posterior longitudinal ligament of the spine

et al. 2001

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Among Japanese, ossification of the posterior longitudinal ligament of the spine (OPLL) is a leading cause of myelopathy, showing ectopic bone formation in the paravertebral ligament. We have provided genetic evidence that the collagen α2 (XI) (COL11A2) locus of chromosome 6 constitutes susceptibility for OPLL. Five distinct single nucleotide polymorphisms (SNPs), identified in COL11A2, were combined to construct possible haplotypes by the use of a maximum likelihood program. Estimated haplotype frequency was compared in OPLL patients and non-OPLL controls. We report a gender-specific association of the COL11A2 haplotype with OPLL. The frequency of the most commonly observed haplotype was significantly higher in male patients (P ϭ 0.0003) compared with controls, but not in female patients (P ϭ 0.21). OPLL is predominantly observed in males, with a prevalence ratio of 2 : 1, and our gender-specific associations indicate that genetic factors involving COL11A2 play a specific role in the etiology of OPLL exclusively in males.

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Human Retinoic X Receptor β: Complete Genomic Sequence and Mutation Search for Ossification of Posterior Longitudinal Ligament of the Spine

Cited by 58 publications

References 24 publications

The genetics of ossification of the posterior longitudinal ligament

The genetics of ossification of the posterior longitudinal ligament

A Functional RNAi Screen for Runx2-Regulated Genes Associated With Ectopic Bone Formation in Human Spinal Ligaments

Gender-specific haplotype association of collagen α2 (XI) gene in ossification of the posterior longitudinal ligament of the spine

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