Over 150 structural defects in the helical region of either of the two type I collagen chains have been described. These defects are associated with the full clinical range of osteogenesis imperfecta (OI), from lethal to mild. We report here the biochemical and molecular characteristics of type I collagen from two siblings referred for assessment of juvenile osteoporosis.

Patient 1 (an 11-year-old male) and Patient 2 (a 7-year-old female) presented with a history of back pain. Radiographs showed multiple compression fractures throughout the thoracic and lumbar spines of both children. Lumbar bone density was strikingly decreased. Skull films showed no wormian bones. The children have some findings overlapping with OI, including neuro-sensory hearing loss, hyperlaxity and minimally blue sclerae. However, neither child has incurred the long bone fractures characteristic of OI and both have carried the diagnosis of juvenile osteoporosis.

Skin fibroblast cultures from both patients produced electrophoretically abnormal type I collagen which appeared as slightly broadened bands with delayed migration of the baseline. A mismatch was detected in the COL1A2 RNA by RNase A cleavage of RNA/RNA hybrids in the region encoding amino acids 249-525. Mutant and normal alleles were separated by RNase A digestion of DNA/RNA hybrids using cloned PCR fragments from this region. DNA sequence analysis of clones harboring the mutant allele identified a missense mutation(G1715N>A) which predicts the substitution of arginine for glycine at position 436 in the helical domain of the type I collagen alpha 2 chain(G436R). The presence of the same heterozygous mutation in two siblings strongly suggests that one parent is a germline mosaic carrier and that the siblings display the full phenotype. Both parents are clinically normal and will be tested for mosaicism. Taken together, the clinical, biochemical and molecular findings in these patients extend the phenotype associated with mutations in type I collagen.