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 proα1(I) chain of type I collagen

J. R. Shapiro, M. L. Stover, V. E. Burn, M. B. McKinstry, A. L. Burshell, S. D. Chipman, D. W. Rowe

Research output: Contribution to journalArticle

Abstract

Mutations affecting the proα1(I) or proα2(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 α1(I) and α1(III). This band merged with the normal α-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 α1(I) cDNA hybrids was detected by chemical cleavage with hydroxylamine:piperidine. The cysteine substitution was thus localized to α1(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.

Original languageEnglish (US)
Pages (from-to)567-573
Number of pages7
JournalJournal of Clinical Investigation
Volume89
Issue number2
DOIs
StatePublished - Jan 1 1992

Keywords

  • Bone
  • Heritable disorder
  • Joint laxity
  • Osteoporosis
  • Sclerae

ASJC Scopus subject areas

  • Medicine(all)

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