Genetic studies from our group has shown that mutations in the genes encoding either of two type I procollagen chaperones, FKBP10 (which encodes the FKBP65 protein) or SERPINH1 (which encodes HSP47), produce severe, recessively inherited forms of OI. Furthermore, we have determined that the two proteins form a complex acting on type I procollagen trimers in the endoplasmic reticulum (ER) and whose function is essential for normal type I procollagen biogenesis. Abrogation of the complex function leads to an altered cellular phenotype with dilated ER, aggregates of intracellular type I procollagen, sequestering of chaperone complex components and abnormal PLOD2-dependent cross-linking. Through the use of mutant FKBP65 and HSP47 cell lines, we have established that PLOD2 is also a member of this newly identified chaperone complex and identifies chaperone dysfunction as a new mechanism of disease in OI. These studies will primarily use newly generated mouse models, complemented by studies in human OI tissues to establish a currently unappreciated mechanistic paradigm for type I procollagen synthesis and a detailed understanding of how OI results from defects in this process. This is a paradigm shift in our understanding of type I procollagen synthesis from the viewpoint of how LH2 modifies or has access to type I procollagen and provides insight into how OI with contractures, also known as Bruck syndrome, can result from mutations in either FKBP10 or PLOD2. The proposed experiments are significant because they have the potential to have an extensive impact on our understanding of the role of telopeptide cross-linking plays in the generation of a functional extracellular matrix and will be essential to understanding and tailoring therapeutics in the context of altered bone matrix on downstream function of bone and associated tissues.

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Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
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Baylor College of Medicine
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Hudson, David M; Archer, Marilyn; King, Karen B et al. (2018) Glycation of type I collagen selectively targets the same helical domain lysine sites as lysyl oxidase-mediated cross-linking. J Biol Chem 293:15620-15627
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
Cundy, Tim; Dray, Michael; Delahunt, John et al. (2018) Mutations That Alter the Carboxy-Terminal-Propeptide Cleavage Site of the Chains of Type I Procollagen Are Associated With a Unique Osteogenesis Imperfecta Phenotype. J Bone Miner Res 33:1260-1271
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
Duran, Ivan; Martin, Jorge H; Weis, Mary Ann et al. (2017) A Chaperone Complex Formed by HSP47, FKBP65, and BiP Modulates Telopeptide Lysyl Hydroxylation of Type I Procollagen. J Bone Miner Res 32:1309-1319
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
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
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

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