An osteopenic nonfracture syndrome with features of mild osteogenesis imperfecta associated with the substitution of a cysteine for glycine at triple helix position 43 in the pro alpha 1(I) chain of type I collagen.

Abstract

Mutations affecting the proal(I) or proa2(I) collagen genes have been identified in each of the major clinical types of osteogenesis imperfecta. This study reports the presence of a heritable connective tissue disorder in a family with an osteopenic syndrome which has features of mild osteogenesis imperfecta but was considered idiopathic osteoporosis in the proband. At age 38, while still premenopausal, she was found to have osteopenia, short stature, hypermobile joints, mild hyperelastic skin, mild scoliosis, and blue sclerae. There was no history of vertebral or appendicular fracture. Hip and vertebral bone mineral density measurements were consistent with marked fracture risk. Delayed reduction SDS-PAGE of pepsin-digested collagens from dermal fibroblast cultures demonstrated an anomalous band migrating between al(I) and al(III). This band merged with the normal a-chains upon prereduction, indicating an unexpected cysteine residue. Cyanogen bromide peptide mapping suggested that the mutation was in the smaller NH2-terminal peptides. cDNA was reverse transcribed from mRNA and amplified by the polymerase chain reaction. A basepair mismatch between proband and control al(I) cDNA hybrids was detected by chemical cleavage with hydroxylamine:piperidine. The cysteine substitution was thus localized to al(I) exon 9 within the cyanogen bromide 4 peptide. Nucleotide sequence analysis localized a G -* T point mutation in the first position of helical codon 43, replacing the expected glycine (GGT) residue with a cysteine (TGT). The prevalence of similar NH2-terminal mutations in subjects with this phenotype which clinically overlaps idiopathic osteoporosis remains to be determined. (J. Clin. Invest. 1992.

Type I Collagen Racemization and Isomerization and the Risk of Fracture in Postmenopausal Women: The OFELY Prospective Study

“…(22)(23)(24) Although most OI patients have subnormal BMD, some have decreased bone strength but normal BMD, (25) providing evidence that type I collagen structure may be related to changes in mechanical strength independently of BMD.…”

Genetic Determinants of Bone Mass

“…Alterations in COL1 production and structure lead to osteogenesis imperfecta, an inherited brittle-bone disorder characterized by fractures, osteopenia and abnormal bone matrix, and several reports suggest a clinical overlap between osteogenesis imperfecta and osteoporosis [157, 158]. However, causative mutations in any COL1 gene have only been identified in a few isolated cases [157, 158, 159]. Transgenic mice with mutations in COL1 genes have been shown to develop bone fragility [160].…”

Defective splicing of mRNA from one COL1A1 allele of type I collagen in nondeforming (type I) osteogenesis imperfecta.

“…For mutations in the a I (I) chain (COLlA 1), there appears to be a positional effect in which those at the COOH terminus are more likely to result in severe disease than those at the NH2 terminus (7). In fact, substitutions for glycine have been identified near the NH2-terminal end ofthe triple helix that result in nondeforming bone disease (type I 01) and heritable osteoporosis (8). Mutations within the a2 (I) chain (COL I A2 gene) that produce mild 01 or osteoporosis (9) do not always occur at the NH2-terminal end of the chain (10).…”