Intron-mediated recombination may cause a deletion in an α1 type I collagen chain in a lethal form of osteogenesis imperfecta

Abstract

To understand the nature of the mutation in type I collagen genes in cells from an infant with the perinatal lethal form of osteogenesis imperfecta (type II), we cloned and sequenced almost 2 kilobases of a normal α1(I) collagen gene and the corresponding region of a mutant α1(I) gene from cell strain CRL 1262. The mutant gene had undergone recombination between two non-homologous introns, which resulted in the loss of three exons coding for 84 amino acids in the triplehelical domain. The deletion predicted the loss of amino acid residues surrounding and including the methionine at the junction between the CNBr peptides α1(I) CB8 and α1(I) CB3, a result confirmed by analysis of the cleavage peptides from the product of the mutant gene. Although large deletions from collagen genes are uncommon causes of the osteogenesis imperfecta type II phenotype, analysis of the de novo change in gene structure in this cell strain suggests that similar rearrangements may have occurred during the evolution of the large collagen genes.