Osteogenesis imperfecta is an inherited disorder, characterize by bone fragility, which commonly results from a defect in the synthesis or structure of type I collagen.
The aims of this proposal are 1) to characterize point mutations, deletions, and duplications in the genes encoding type I collagen (COL1A1 and COL1A2) which produce the perinatal lethal form of this disease in families in which there is sporadic (single) occurrence of the phenotype; 2) to characterize mutations in infants with perinatal lethal OI from families in which there has been recurrence of the disease; 3) to identify and analyze mutations in families with the mild to moderate OI type IV phenotype; and 4) to determine the relationship between the nature and locations of the mutations and the biochemical consequences of the mutations on the behavior of type I collagen molecules which incorporate an abnormal chain. Mutations will be identified by isolation of the type I collagen genes from affected individuals and determination of DNA sequences in the regions of the genes encoding the protein. Biochemical analysis of type I collagen molecules produced by the cells will include determination of the degree of post-translational modification, efficiency of secretion, thermal stability, rate of triple helix formation, and contribution to the extracellular matrix of the abnormal molecules. The results of the proposed work will facilitate genetic counseling and prenatal diagnosis for families at risk for this disease, and will apply to related diseases in which only elements of the OI phenotype are present or in which similar mutations occur in other collagen types.
