In close concert with projects 1 and 2, we seek common molecular features of abnormal bone collagen expression in tissue from mice and human cases of osteogenesis imperfecta (01) caused by mutations in genes encoding the CRTAP/P3H1/CYPB and FKBP10/HSP47 complexes and newly identified genes causing recessive 01. The significance and inter-relationships of defective prolyl 3-hydroxylation, associated post-translational over modification of lysine residues and abnormal cross-linking are the focus and basis of hypothesis-driven studies. One goal is to thoroughly test the possibility that abnormal post-translational chemistry, and in particular cross-linking, underlies the brittle bone phenotype. Though the focus is novel recessive forms of 01, the significance of the findings is likely to extend across all forms of 01.
The specific aims are directed at establishing the cross-linking phenotype of bone collagen from mouse models and available human 01 cases, seeking a common pathology and common underlying mechanism.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
5P01HD070394-03
Application #
8508693
Study Section
Special Emphasis Panel (ZHD1-DSR-Y)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
3
Fiscal Year
2013
Total Cost
$282,901
Indirect Cost
$36,645
Name
Baylor College of Medicine
Department
Type
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
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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
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
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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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