Osteogenesis imperfecta (OI) is a heritable disorder of connective tissue, characterized by bone fragility, which primarily results from dominant mutations in the type I collagen genes. The principal objective of the proposed work is to understand the mechanism, parental origin, and developmental timing of type I collagen gene mutations that produce this disease. Specifically, the goals are: A) To determine parental origin and the frequency of parental mosaicism in sporadic cases of OI. The proportion of families in which one parent is mosaic, in their somatic tissues and/or germline, for the new dominant mutation identified in their affected offspring will be determined. The parental and grandparental origin of the mutations will be determined by linkage to informative polymorphic markers. B) To determine the molecular basis of recurrence in families with non-lethal forms of OI. The hypothesis that, like lethal OI, recurrence of non-lethal forms of OI to normal parents primarily results from mosaicism for a dominant mutation in one parent will be tested. C) To determine the consequences of novel type I collagen gene mutations on the biochemical properties of abnormal type I collagen molecules. These studies will utilize unique human mutations to examine specific features of type I collagen function. As a result of this work, novel and efficient strategies for characterizing mutations will be developed which will make molecular diagnosis available to a high proportion of OI families and improve clinical care. Our studies will also yield better markers for linkage analysis in families with dominantly-inherited OI, making such studies available to most OI families. Advances in the methods for screening type I collagen genes for mutations will be applicable to other known collagen disorders and to the analysis of collagen genes in disorders for which the basic defect is unknown. Understanding mechanism and developmental timing of mutations in the type I collagen genes will markedly improve genetic counseling, and will advance our concepts of human mutations and the genesis of human genetic disease.
