A heterozygous single base change in exon 49 of COL1A1, which converted the codon for pro alpha 1(I) carboxyl-terminal propeptide residue 94 from tryptophan (TGG) to cysteine (TGT) was identified in a baby with lethal osteogenesis imperfecta (OI64). The C-propeptide mutations in OI64 and in another lethal osteogenesis imperfecta cell strain (OI26), which has a frameshift mutation altering the sequence of the carboxyl-terminal half of the propeptide (Bateman, J. F., Lamande, S. R., Dahl, H.-H. M., Chan, D., Mascara, T. and Cole, W. G. (1989) J. Biol. Chem. 264, 10960-10964), disturbed procollagen folding and retarded the formation of disulfide-linked trimers. Although assembly was delayed, the presence of slowly migrating, overmodified alpha 1(I) and alpha 2(I) chains indicated that mutant pro alpha 1(I) could associate with normal pro alpha 1(I) and pro alpha 2(I) to form pepsin-resistant triple-helical molecules, a proportion of which were secreted. Further evidence of the aberrant folding of mutant procollagen in OI64 and OI26 was provided by experiments demonstrating that the endoplasmic reticulum resident molecular chaperone BiP, which binds to malfolded proteins, was specifically bound to type I procollagen and was coimmunoprecipitated in the osteogenesis imperfecta cells but not control cells. Experiments with brefeldin A, which inhibits protein export from the endoplasmic reticulum, demonstrated that unassembled mutant pro alpha 1(I) chains were selectively degraded within the endoplasmic reticulum resulting in reduced collagen production by the osteogenesis imperfecta cells. This biosynthetic deficiency was reflected in the inability of OI64 and OI26 cells to produce a substantial in vitro collagenous matrix when grown in the continuous presence of ascorbic acid to allow collagen matrix formation. Both these carboxyl-terminal propeptide mutants showed a marked reduction in collagen accumulation to 20% (or less) of control cultures, comparable to the reduced collagen content of tissues from OI26.

No abstract

No abstract

We describe 22 patients who presented between the ages of 4 and 14 years with gradual onset of malaise and pain at the sites of multiple bone lesions. The symptoms from the bone lesions were sometimes sequential in onset and often relapsing. The radiological findings were typical of osteomyelitis. Radioisotope bone scans identified some clinically silent lesions. Bone biopsies were performed in 20 patients and the changes of osteomyelitis were seen in 17; microbiological culture was positive in only one. Seven patients had polyarthritis, two had palmoplantar pustulosis and one had psoriasis. Some symptomatic relief was obtained with anti-inflammatory agents and, to a less extent, with antibiotics. No patient had primary immunodeficiency. The mean duration of symptoms from the bone lesions was two years (1 to 4). When arthritis was present the joint symptoms lasted considerably longer (mean 7 years; range 4 to 10). The long-term prognosis was generally good. There was no evidence of altered bone growth or abnormal joint development. One patient developed a progressive kyphosis requiring fusion, but no other surgical intervention was necessary.