A Mutation in COL9A1 Causes Multiple Epiphyseal Dysplasia: Further Evidence for Locus Heterogeneity

Abstract

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.

Identification of cartilage oligomeric matrix protein (COMP) gene mutations in patients with pseudoachondroplasia and multiple epiphyseal dysplasia

“…For the Thr585Met mutation, there were two reports concerning their produced phenotype. In one report (Briggs et al 1998), the patient with the Thr585Met mutation produced the PSACH phenotype, in the other report (Czarny-Ratajczak et al 2001), the patient with Thr585Met produced the MED phenotype, which was the same as our observation. The Asp385Asn mutation was a recently identified mutation (Mabuchi et al 2003), which produced the MED phenotype.…”

“…Some mutations in COMP can lead to a form of multiple epiphyseal dysplasia (MED; MIM 132400), a milder form of the skeletal dysplasia. MED has also been associated with mutations in the genes coding for a1, a2, and a3 chains of collagen IX, SLC26A2 and matrilin-3 (Chapman et al 2001;Czarny-Ratajczak et al 2001).The predominant features of MED are mild short stature and stiff or painful joints. The phenomenon of overlap between the mild form of PSACH and the severe form of MED has been noticed not only in clinical and radiographic characteristics but also in biochemical findings (Manabe et al 1998;Stanescu et al 1993).…”

“…Some mutations in COMP can lead to a form of multiple epiphyseal dysplasia (MED; MIM 132400), a milder form of the skeletal dysplasia. MED has also been associated with mutations in the genes coding for a1, a2, and a3 chains of collagen IX, SLC26A2 and matrilin-3 (Chapman et al 2001;Czarny-Ratajczak et al 2001).…”

Associations of 25 structural, degradative, and inflammatory candidate genes with lumbar disc desiccation, bulging, and height narrowing

“…Interestingly, SNP rs696990, which is located 9.2 kb 5Ј of the COL9A1 gene, provided the strongest evidence of association with disc signal intensity in this study. Mutations in the coding region of the COL9A1 gene have been identified in affected members of families with multiple epiphyseal dysplasia and a novel autosomal-recessive form of Stickler syndrome (35,36). In addition, polymorphisms in the COL9A1 gene have recently been reported to be associated with disc degeneration in mice (37).…”

Mutations in the known genes are not the major cause of MED; distinctive phenotypic entities among patients with no identified mutations

“…The overall mutation frequency obtained here is supported by another, slightly larger study in which similar mutation frequencies were obtained. 13 We failed to identify mutations in any of these genes in 19 of the 29 patients (64%). There are several possible explanations for the low mutation frequency.…”