Heterozygosity for a large deletion in the α2(I) collagen gene has a dramatic effect on type I collagen secretion and produces perinatal lethal osteogenesis imperfecta

M. C. Willing, D. H. Cohn, B. Starman, K. A. Holbrook, C. R. Greenberg, P. H. Byers

Research output: Contribution to journalArticle

42 Scopus citations

Abstract

We characterized a de novo 4.5 kilobase pair deletion in the paternally derived α2(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 proα2(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-α2(I) chain and normal pro-α1(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.

Original languageEnglish
Pages (from-to)8398-8404
Number of pages7
JournalJournal of Biological Chemistry
Volume263
Issue number17
StatePublished - Jan 1 1988
Externally publishedYes

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