Intervertebral disc disease is one of the most common musculoskeletal disorders. A number of environmental and anthropometric risk factors may contribute to it, and recent reports have suggested the importance of genetic factors as well. The COL9A2 gene, which codes for one of the polypeptide chains of collagen IX that is expressed in the intervertebral disc, was screened for sequence variations in individuals with intervertebral disc disease. The analysis identified a putative disease-causing sequence variation that converted a codon for glutamine to one for tryptophan in six out of the 157 individuals but in none of 174 controls. The tryptophan allele cosegregated with the disease phenotype in the four families studied, giving a lod score (logarithm of odds ratio) for linkage of 4.5, and subsequent linkage disequilibrium analysis conditional on linkage gave an additional lod score of 7.1.

This study led to the identification of a novel common genetic risk factor for LDD, confirming that genetic risk factors likely play a significant role in LDD.

Multiple epiphyseal dysplasia (MED) is an autosomal dominantly inherited chondrodysplasia. It is clinically highly heterogeneous, partially because of its complex genetic background. Mutations in four genes, COL9A2, COL9A3, COMP, and MATR3, all coding for cartilage extracellular matrix components (i.e., the alpha2 and alpha 3 chains of collagen IX, cartilage oligomeric matrix protein, and matrilin-3), have been identified in this disease so far, but no mutations have yet been reported in the third collagen IX gene, COL9A1, which codes for the alpha1(IX) chain. MED with apparently recessive inheritance has been reported in some families. A homozygous R279W mutation was recently found in the diastrophic dysplasia sulfate transporter gene, DTDST, in a patient with MED who had a club foot and double-layered patella. The series consisted of 41 probands with MED, 16 of whom were familial and on 4 of whom linkage analyses were performed. Recombination was observed between COL9A1, COL9A2, COL9A3, and COMP and the MED phenotype in two of the families, and between COL9A2, COL9A3, and COMP and the phenotype in the other two families. Screening of COL9A1 for mutations in the two probands from the families in which this gene was not involved in the recombinations failed to identify any disease-causing mutations. The remaining 37 probands were screened for mutations in all three collagen IX genes and in the COMP gene. The probands with talipes deformities or multipartite patella were also screened for the R279W mutation in DTDST. The analysis resulted in identification of three mutations in COMP and one in COL9A1, but none in the other two collagen IX genes. Two of the probands with a multipartite patella had the homozygous DTDST mutation. The results show that mutations in COL9A1 can cause MED, but they also suggest that mutations in COL9A1, COL9A2, COL9A3, COMP, and DTDST are not the major causes of MED and that there exists at least one additional locus.

Multiple epiphyseal dysplasia (MED), an autosomal dominant osteochondrodysplasia, is a clinically and genetically heterogeneous disorder characterized by mild short stature and early-onset osteoarthritis. The phenotypic spectrum includes the mild Ribbing type, the more severe Fairbank type, and some unclassified forms. Linkage studies have identified two loci for MED. One of these, EDM1, is on chromosome 19, in a region that contains the cartilage oligomeric matrix protein (COMP) gene. Mutations have been identified in this gene in patients with the Ribbing type, the Fairbank type, and unclassified forms of MED. The second locus, EDM2, maps to chromosome 1, in a region spanning COL9A2. Recently, a splice-site mutation was found in COL9A2, causing skipping of exon 3 in one family with MED. Because of the exclusion of the EDM1 and EDM2 loci in some families, the existence of a third locus has been postulated. We report here one family with MED, evaluated clinically and radiologically and tested for linkage with candidate genes, including COMP, COL9A1, COL9A2, and COL9A3. No linkage was found with COMP, COL9A1, or COL9A2, but an inheritance pattern consistent with linkage was observed with COL9A3. Mutation analysis of COL9A3 identified an A-->T transversion in the acceptor splice site of intron 2 in affected family members. The mutation led to skipping of exon 3 and an in-frame deletion of 12 amino acid residues in the COL3 domain of the alpha3(IX) chain and thus appeared to be similar to that reported for COL9A2. This is the first disease-causing mutation identified in COL9A3. Our results also show that COL9A3, located on chromosome 20, is a third locus for MED.

IntroductionDegeneration of the intervertebral disc is a process that begins early in life and is a consequence of a various intrinsic and extrinsic factors as well as of normal ageing. Environmental factors appear to explain only a minor part of individual variation in pathologic changes in the disc, while the major part remains unexplained [4,5,34]. Epidemiological studies of twins suggest that inheritance is the largest single determinant of disc degeneration (DD) [5,27].Recently, an association between DD and polymorphisms in the vitamin-D receptor [37,38] Abstract Disc degeneration is a complex condition in which environmental factors and multiple genes are expected to act together to determine the degenerative phenotype. Recently associations of COL9A2 (Trp2 allele) and COL9A3 (Trp3 allele) polymorphisms with lumbar disc disease characterized by sciatica have been reported. However, it is not known whether the Trp2 or Trp3 alleles contribute to disc degeneration (DD). In this study, the association between the collagen genes polymorphisms and lumbar DD was investigated. Furthermore, the influence of the IL1b(C 3954 -T) polymorphism on the association of collagen genes polymorphisms with DD was examined. Lumbar intervertebral discs of 135 middle-aged occupationally active men were evaluated with magnetic resonance imaging, using decreased signal intensity of the nucleus pulposus, disc bulges, and decreased disc height as signs of degeneration. Blood samples were analysed for the presence of COL9A3 and COL9A2 tryptophan alleles (Trp3 and Trp2 alleles). The COL11A2, COL2A1 and IL-1b(C 3954 -T) polymorphisms were also analysed. Multivariate logistic regression analysis allowing for occupation and body mass index showed that the carriage of the Trp3 allele in the absence of the IL1bT 3954 allele increased the risk of dark nucleus pulposus (OR 7.0, 95% CI 1.3-38.8) and joint occurrence of degenerative changes (OR 8.0, 95% CI 1.4-44.7). There was no effect of the Trp3 allele on DD in the presence of the IL-1bT 3954 allele. The carriers of the COL11A2 minor allele had an increased risk of disc bulges (OR 2.1, 95% CI 1.0-4.2) as compared with non-carriers. The results suggest that the effect of the COL9A3 gene polymorphism on DD might be modified by the IL-1b gene polymorphism.

The effect of obesity on lumbar disc degeneration seems to be modified by the collagen IX gene polymorphism, so that people who carry the Trp3 allele are at increased risk if they are persistently obese.

Early-onset OA demonstrates locus and allelic heterogeneity since the identified variations were in three different collagen genes and each of the six probands had a different mutation. It is also possible that some OA cases represent the mild end of the chondrodysplasia phenotypic spectrum. The major susceptibility alleles in this form of OA, however, remain to be identified.

Multiple epiphyseal dysplasia (MED) is an osteochondrodysplasia characterized clinically by mild short stature and early-onset degenerative joint disease and radiographically by epiphyseal hypoplasia/dysplasia. MED is genetically heterogeneous, with autosomal dominant cases resulting from mutations in at least three genes: the cartilage oligomeric matrix protein (COMP) gene (EDM1) and the COL9A2 (EDM2) and COL9A3 (EDM3) genes of type IX procollagen. We present here a comparison of the radiographic phenotypes of MED patients with type IX collagen gene mutations and those with COMP gene mutations. We reviewed radiographs from two patients with MED produced by COMP mutations, two families with COL9A2 mutations, and one family with a mutation in COL9A3. The data demonstrated that the patients with type IX collagen defects had more severe joint involvement at the knees and relative hip sparing, while the patients with COMP mutations had significant involvement at the capital femoral epiphyses and irregular acetabuli. This pattern of joint involvement was consistent regardless of overall degree of severity of the phenotype.