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. 2003 Dec;62(12):1208–1214. doi: 10.1136/ard.2003.008334

Sequence variations in the collagen IX and XI genes are associated with degenerative lumbar spinal stenosis

N Noponen-Hietala, E Kyllonen, M Mannikko, E Ilkko, J Karppinen, J Ott, L Ala-Kokko
PMCID: PMC1754404  PMID: 14644861

Abstract

Background: Degenerative lumbar spinal stenosis (LSS) is usually caused by disc herniation or degeneration. Several genetic factors have been implicated in disc disease. Tryptophan alleles in COL9A2 and COL9A3 have been shown to be associated with lumbar disc disease in the Finnish population, and polymorphisms in the vitamin D receptor gene (VDR) (FokI and TaqI), the matrix metalloproteinase-3 gene (MMP-3) and an aggrecan gene (AGC1) VNTR have been reported to be associated with disc degeneration. In addition, an IVS6-4 a>t polymorphism in COL11A2 has been found in connection with stenosis caused by ossification of the posterior longitudinal ligament in the Japanese population.

Objective: To study the role of genetic factors in LSS.

Methods: 29 Finnish probands were analysed for mutations in the genes coding for intervertebral disc matrix proteins, COL1A1, COL1A2, COL2A1, COL9A1, COL9A2, COL9A3, COL11A1, COL11A2, and AGC1. VDR and MMP-3 polymorphisms were also analysed. Sequence variations were tested in 56 Finnish controls.

Results: Several disease associated alleles were identified. A splice site mutation in COL9A2 leading to a premature translation termination codon and the generation of a truncated protein was identified in one proband, another had the Trp2 allele, and four others the Trp3 allele. The frequency of the COL11A2 IVS6-4 t allele was 93.1% in the probands and 72.3% in controls (p = 0.0016). The differences in genotype frequencies for this site were less significant (p = 0.0043).

Conclusions: Genetic factors have an important role in the pathogenesis of LSS.

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Figure 1 .

Figure 1

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T2 weighted transaxial MRI scans (TR 6000 ms/TE 105 ms) of probands 2 (A), 10 (B), and 23 (C). (A) A hypertrophic band is seen at the L2–3 disc level and caudally at L3–4 (white arrows). Both disc and end plate degeneration are seen at all lumbar levels. (B) The scan shows OPLL at the L4 vertebral level (white arrow). This proband also had severe disc and end plate degeneration at multiple lumbar levels. (C) The scan indicates severe disc degeneration at multiple lumbar levels, and a Schmorl's node at L2–3.

Figure 2 .

Figure 2

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Agarose gel electrophoresis of α2(IX) RT-PCR products. Total RNA from proband 23 was analysed by RT-PCR using primer pairs corresponding to exons 23 and 30 (lane 2), or exons 24 and 29 (lane 3), as indicated in "Materials and methods". The analysis showed two products of about 550 bp and 460 bp (lane 2) and 420 bp and 340 bp (lane 3). Sequencing indicated that the lower molecular weight products contained the wild-type sequence, whereas the higher molecular weight products also contained intron 26. Lane 1 contains a 100 bp ladder.

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