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.
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.
Willing
M C
MC
Department of Medicine, University of Washington, Seattle 98195.
Cohn
D H
DH
Starman
B
B
Holbrook
K A
KA
Greenberg
C R
CR
Byers
P H
PH
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
D003094:Collagen