Substitution of cysteine for glycine within the carboxyl-terminal telopeptide of the alpha 1 chain of type I collagen produces mild osteogenesis imperfecta.
We have characterized a mutation that produces mild, dominantly inherited osteogenesis imperfecta. Half of the alpha 1 (I) chains of type I collagen synthesized by cells from an affected individual contain a cysteine residue in the 196-residue carboxyl-terminal cyanogen bromide peptide of the triple-helical domain (Steinmann, B., Nicholls, A., and Pope, F. M. (1986) J. Biol. Chem. 261, 8958-8964). Unexpectedly, sequence determined from a proteolytic fragment of the alpha 1 (I) chain derived from procollagen molecules synthesized in the presence of both [3H]proline and [35S]cysteine indicated that the cysteine is located at the third residue carboxyl-terminal to the triple-helical domain, normally a glycine. The nucleotide sequence of a fragment amplified from genomic DNA confirmed the location of the cysteine residue and showed that the mutation was a single nucleotide change in one COL1A1 allele. This represents a new class of mutations, point mutations outside the triple-helical domain of the chains of type I collagen, that produce the osteogenesis imperfecta phenotype.
Cohn
D H
DH
Department of Pathology, University of Washington, Seattle 98195.
Apone
S
S
Eyre
D R
DR
Starman
B J
BJ
Andreassen
P
P
Charbonneau
H
H
Nicholls
A C
AC
Pope
F M
FM
Byers
P H
PH
D000483:Alleles; D000595:Amino Acid Sequence; D001483:Base Sequence; D002478:Cells, Cultured; D003094:Collagen / Q000235:genetics*; D003545:Cysteine; D005347:Fibroblasts / Q000378:metabolism; D005784:Gene Amplification; D005796:Genes; D005998:Glycine; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D010013:Osteogenesis Imperfecta / Q000235:genetics*; D010446:Peptide Fragments / Q000032:analysis; D012867:Skin / Q000378:metabolism
D010446:Peptide Fragments; D003094:Collagen; D003545:Cysteine; D005998:Glycine