A mutation in the alpha 3 chain of type IX collagen causes autosomal dominant multiple epiphyseal dysplasia with mild myopathy

Multiple epiphyseal dysplasia (MED) is a degenerative cartilage condition s hown in some cases to be caused by mutations in genes encoding cartilage ol igomeric matrix protein or type IX collagen. We studied a family with autos omal dominant MED affecting predominantly the knee joints and a mild proxim al myopathy. Genetic linkage to the COL9A3 locus on chromosome 20q13.3 was established with a peak log(10) odds ratio for linkage score of 3.87 for ma rkers D20S93 and D20S164. Reverse transcription-PCR performed on the muscle biopsy revealed aberrant mRNA lacking exon 3, which predicted a protein la cking 12 amino acids from the COL3 domain of alpha 3(IX) collagen. Direct s equencing of genomic DNA confirmed the presence of a splice acceptor mutati on in intron 2 of the COL9A3 gene (intervening sequence 2, C-A, -1) only in affected family members. By electron microscopy, chondrocytes from epiphys eal cartilage exhibited dilated rough endoplasmic reticulum containing line ar lamellae of alternating electron-dense and electron-lucent material, ref lecting abnormal processing of mutant protein. Type IX collagen chains appe ared normal in size and quantity but showed defective cross-linking by West ern blotting. The novel phenotype of MED and mild myopathy is likely caused by a dominant-negative effect of the exon 3-skipping mutation in the COL9A 3 gene. Patients with MED and a waddling gait but minimal radiographic hip involvement should be evaluated for a primary myopathy and a mutation in ty pe IX collagen.