Identification of novel pro-alpha 2(IX) collagen gene mutations in two families with distinctive olgo-epiphyseal forms of multiple epiphyseal dysplasia

Multiple epiphyseal dysplasia (MED) is a genetically heterogeneous disorder with marked clinical and radiographic variability. Traditionally, the mild "Ribbing" and severe "Fairbank" types have been used to define a broad phe notypic spectrum. Mutations in the gene encoding cartilage oligomeric-matri x protein have been shown to result in several types of MED, whereas mutati ons in the gene encoding the alpha 2 chain of type IX collagen (COL9A2) hav e so far been found only in two families with the Fairbank type of MED. Typ e IX collagen is a heterotrimer of pro-alpha chains derived from three dist inct genes-COL9A1, COL9A2, and COL9A3. In this article, we describe two fam ilies with distinctive oligo-epiphyseal forms of MED, which are heterozygou s for different mutations in the COL9A2 exon 3/intron 3 splice-donor site. Both of these mutations result in the skipping of exon 3 from COL9A2 mRNA, but the position of the mutation in the splice-donor site determines the st ability of the mRNA produced from the mutant COL9A2 allele.