A mutation in COL9A1 causes multiple epiphyseal dysplasia: Further evidence for locus heterogeneity

Multiple epiphyseal dysplasia (MED) is an autosomal dominantly inherited ch ondrodysplasia. It is clinically highly heterogeneous, partially because of its complex genetic background. Mutations in four genes, COL9A2, COL9A3, C OMP, and MATR3, all coding for cartilage extracellular matrix components (i .e., the alpha2 and alpha3 chains of collagen IX, cartilage oligomeric matr ix protein, and matrilin-3), have been identified in this disease so far, b ut no mutations have yet been reported in the third collagen IX gene, COL9A 1, which codes for the alpha1(IX) chain. MED with apparently recessive inhe ritance has been reported in some families. A homozygous R279W mutation was recently found in the diastrophic dysplasia sulfate transporter gene, DTDS T, in a patient with MED who had a club foot and double-layered patella. Th e series consisted of 41 probands with MED, 16 of whom were familial and on 4 of whom linkage analyses were performed. Recombination was observed betw een COL9A1, COL9A2, COL9A3, and COMP and the MED phenotype in two of the fa milies, and between COL9A2, COL9A3, and COMP and the phenotype in the other two families. Screening of COL9A1 for mutations in the two probands from t he families in which this gene was not involved in the recombinations faile d 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 s creened for the R279W mutation in DTDST. The analysis resulted in identific ation of three mutations in COMP and one in COL9A1, but none in the other t wo collagen IX genes. Two of the probands with a multipartite patella had t he 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 l east one additional locus.