Tandem Duplication Within a Type II Collagen Gene (COL2A1) Exon in an Individual with Spondyloepiphyseal Dysplasia

We have characterized a mutation in the type II collagen gene (COL2A1) that produces a form of spondyloepiphyseal dysplasia. The mutation is an internal tandem duplication of 45 base pairs within exon 48 and results in the addition of 15 amino acids to the triple-helical domain of the α1 chains of type II collagen derived from the abnormal allele. Although the repeating (Gly-Xaa-Yaa)nmotif that characterizes the triple-helical domain is preserved, type II collagen derived from cartilage of the affected individual contains a population with excessive posttranslational modification, consistent with a disruption in triple-helix structure. The mutation is not carried by either parent, indicating that the phenotype in the affected individual is due to a new dominant mutation. DNA sequence homology in the area of the duplication suggests that the mutation may have arisen by unequal crossover between related sequences, a proposed mechanism in the evolution and diversification of the collagen gene family.