title: Heterozygosity for a large deletion in the alpha 2(I) collagen gene has a dramatic effect on type I collagen secretion and produces perinatal lethal osteogenesis imperfecta.
abstract: We characterized a de novo 4.5 kilobase pair deletion in the paternally derived alpha 2(I) collagen allele (COL1A2) from a patient with perinatal lethal osteogenesis imperfecta. The intron-to-intron deletion removed the seven exons which encode residues 586-765 of the triple helical domain of the chain. Type I procollagen molecules that contain the mutant pro-alpha 2(I) chain have a lower than normal thermal stability, undergo increased post-translational modification amino-terminal to the deletion junction, and are retained within the rough endoplasmic reticulum. The block to secretion appears to result from improper assembly of the triple helix, apparently a consequence of a disruption of charge-charge interactions between the shortened pro-alpha 2(I) chain and normal pro-alpha 1(I) chains. The lethal effect may be due to decreased secretion of normal collagen and secretion of a small amount of abnormal collagen that disrupts matrix formation.
authors: Department of Medicine, University of Washington, Seattle 98195.
authors: M C
authors: MC
authors: Willing
authors: D H
authors: DH
authors: Cohn
authors: B
authors: B
authors: Starman
authors: K A
authors: KA
authors: Holbrook
authors: C R
authors: CR
authors: Greenberg
authors: P H
authors: PH
authors: Byers
mesh_terms: D000483:Alleles; D002478:Cells, Cultured; D002872:Chromosome Deletion; D003094:Collagen / Q000235:genetics*; D005091:Exons; D006579:Heterozygote; D006801:Humans; D008854:Microscopy, Electron; D009154:Mutation; D010013:Osteogenesis Imperfecta / Q000235:genetics*; D010449:Peptide Mapping
chemical_list: D003094:Collagen