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.
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.
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|Hudson, David M; Weis, MaryAnn; Rai, Jyoti et al. (2017) P3h3-null and Sc65-null Mice Phenocopy the Collagen Lysine Under-hydroxylation and Cross-linking Abnormality of Ehlers-Danlos Syndrome Type VIA. J Biol Chem 292:3877-3887|
|Machol, Keren; Jain, Mahim; Almannai, Mohammed et al. (2017) Corner fracture type spondylometaphyseal dysplasia: Overlap with type II collagenopathies. Am J Med Genet A 173:733-739|
|Lee, Chae Syng; Fu, He; Baratang, Nissan et al. (2017) Mutations in Fibronectin Cause a Subtype of Spondylometaphyseal Dysplasia with ""Corner Fractures"". Am J Hum Genet 101:815-823|
|Abbott, Megan; Jain, Mahim; Pferdehirt, Rachel et al. (2017) Neonatal fractures as a presenting feature of LMOD3-associated congenital myopathy. Am J Med Genet A 173:2789-2794|
|Marom, Ronit; Jain, Mahim; Burrage, Lindsay C et al. (2017) Heterozygous variants in ACTL6A, encoding a component of the BAF complex, are associated with intellectual disability. Hum Mutat 38:1365-1371|
|Zeng, Huan-Chang; Bae, Yangjin; Dawson, Brian C et al. (2017) MicroRNA miR-23a cluster promotes osteocyte differentiation by regulating TGF-? signalling in osteoblasts. Nat Commun 8:15000|
|Joeng, Kyu Sang; Lee, Yi-Chien; Lim, Joohyun et al. (2017) Osteocyte-specific WNT1 regulates osteoblast function during bone homeostasis. J Clin Invest 127:2678-2688|
|Lim, Joohyun; Grafe, Ingo; Alexander, Stefanie et al. (2017) Genetic causes and mechanisms of Osteogenesis Imperfecta. Bone 102:40-49|
|Madan, Simran; Liu, Wei; Lu, James T et al. (2017) A non-mosaic PORCN mutation in a male with severe congenital anomalies overlapping focal dermal hypoplasia. Mol Genet Metab Rep 12:57-61|
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