The Challenges of Autosomal Recessive and Other New Forms of OI

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DESCRIPTION (provided by applicant): Osteogenesis imperfecta (OI) affects about 1/12,500 individuals throughout the world. This means that there are about 25,000 individuals with this disorder in the United States, the majority of whom have a relatively mild form of the condition and endure a few to dozens of fractures throughout their lifetimes. For the remainder, disability ranges from the need for assists while walking, to the use of motorized wheelchairs or carts throughout their lifetimes, to death in the perinatal period from pulmonary insufficiency as a result of marked underdevelopment and fracture of bones of the chest. More than 90% of individuals with OI have mutations in one of the two genes (COL1A1 and COL1A2) that encode the chains of type I collagen, and these mutations are either inherited in a dominant fashion through several generations or arise de novo in the first affected infant in a family. Recessive inheritance of OI has been postulated in severe forms with recurrence in sibships with unaffected parents. Initially some of these were shown to result from parental mosaicism for dominant mutations in type I collagen genes. In the last three years, however, three genes have been identified (CRTAP, LEPRE1, and Smpd3) in which mutations can lead to recessively inherited forms of OI. Mutations in two of these genes (CRTAP and LEPRE1) have been found to produce OI phenotypes in people. Mutations in Smpd3 result in the fro/fro mouse model of recessive OI. These studies have provided a new background on which to try to understand how mutations result in brittle bones, growth retardation, and skeletal deformity, and should provide the substrate on which to envision and test new forms of treatment for OI, as animal models already exist. This meeting, which is expected to bring some 70 basic scientists, clinical investigators, clinicians, and trainees together, provides the first opportunity to synthesize our understanding of recessively inherited forms of OI, to examine the range of clinical presentation, to understand the roles of the enzymatic systems involved, and to examine how insights gained from both animal and human studies might lead to more effective treatments of recessive forms of OI and of the more common dominantly inherited forms. The Challenges of Autosomal Recessive and Other New Forms of OI will lead to enhanced collaboration among researchers, and to the growing involvement of directors of clinical research centers, all of whom benefit from regular meetings to share information and update their clinical and research strategies. It also will facilitate identification of new OI genes, identify new paths of research to benefit patients, and increase progress of the Linked Clinical Research Centers.