The overall goal of this Program Project is to elucidate the mechanistic basis of a novel group of recessively inherited forms of Osteogenesis Imperfecta (OI) or brittle bone disease that is based on alterations in the post-translational modification and trafficking of collagen. After twenty years where the only identifiable genetic basis of 0I has been structural mutations in type I collagen (encoded by C0L1A1 and C0L1A2 genes), we and others have shown that mutations in components of two complexes (i.e., the prolyl 3- hydroxylase and the FKBP10/HSP47 complexes) required for collagen processing account for up to 10% of cases. More importantly, they identify a potentially novel mechanism for connective tissue disease and underscore the importance of poorly understood but highly conserved evolutionary post-translational mechanisms. Still despite the well documented biochemical activities of these complexes, it has been difficult to clinically distinguish the dominant and recessively inherited forms of 0I. With bone fragility and abnormal connective tissue as the clinical endpoints, we hypothesize that these mutations ultimately lead to common pathogenic mechanisms that integrate cellular, matrix, and signaling defects that ultimately lead to the clinical phenotype. We propose to test this hypothesis by combining genetic, cell biological, and biochemical approaches to analyze novel mouse mutants and human tissues. These approaches will be encompassed by three projects: Project 1 led by Dr. Brendan Lee will be focused on the mouse and human genetic study of the P3H complex. Project 2 led by Drs. Deborah Krakow and Dan Cohn will be focused on mouse and human genetic, and cell biology study of the FKBP10 complex, and Project 3 led by Drs. David Eyre will focus on biochemical analyses of novel mouse and human models of OI and the requirement of prolyl 3-hydroxylation from the collagen perspective. The human genetic studies will supported by the Genomics Core led by Dr. D. Cohn. The implementation and integration of the work will be supported by Dr. B. Lee in the Administrative Core.

Public Health Relevance

Osteogenesis Imperfecta or brittle bone disease is the most common genetic cause of bone fragility in children. We and others have recently shown that there are many different genetic causes. This work will identify the common mechanisms by which mutations cause the clinical condition. In so doing, we hope to identify new therapies and diagnostic tools for distinguishing these conditions.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Program Projects (P01)
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Special Emphasis Panel (ZHD1-DSR-Y (50))
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Javois, Lorette Claire
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Baylor College of Medicine
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Alhamdi, Shatha; Lee, Yi-Chien; Chowdhury, Shimul et al. (2018) Heterozygous WNT1 variant causing a variable bone phenotype. Am J Med Genet A 176:2419-2424
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