Extension of phenotype associated with structural mutations in type T collagen: Siblings with juvenile osteoporosis have an alpha 2(I)Gly436 -> Arg substitution

Mutations in the type I collagen genes have been identified as the cause of all four types of osteogenesis imperfecta (OI), We now report a mutation t hat extends the phenotype associated with structural abnormalities in type I collagen, Two siblings presented with a history of back pain and were dia gnosed with juvenile osteoporosis, based on clinical and radiological exami nation. Radiographs showed decreased lumbar bone density and multiple compr ession fractures throughout the thoracic and lumbar spines of both patients , One child has moderate short stature and mild neurosensory hearing loss. However, neither child has incurred the long bone fractures characteristic of OI, Protein studies demonstrated electrophoretically abnormal type I col lagen in samples from both children. Enzymatic cleavage of RNA:RNA hybrids identified a mismatch in type I collagen alpha 2 (COL1A2) mRNA, DNA sequenc ing of COL1A2 cDNA subclones defined the mismatch as a single-base mutation (1715G --> A) in both children. This mutation predicts the substitution of arginine for glycine at position 436 (G436R) in the helical domain of the alpha 2(I) chain. Analysis of genomic DNA identified the mutation in the as ymptomatic father, who is presumably a germ-line mosaic carrier. The presen ce of the same heterozygous mutation in two siblings strongly suggests that the probands display the full phenotype, Taken together, the clinical, bio chemical, and molecular findings of this study extend the phenotype associa ted with type I collagen mutations to cases with only spine manifestations and variable short stature into adolescence.