A poorly understood collagen post-translational modification has been 3-prolyl-hydroxylation (P3H) converting proline to 3-hydroxy proline (3-Hyp). It occurs uniquely in the fibrillar collagens, i.e., types I, II and III collagen, at only one proline position, but abundantly in other collagens such as network collagens, i.e., type IV collagen, where it occurs in up to 10% of residues. This begs the question of whether 3-Hyp residues may serve divergent biological functions in different settings and tissues. In recent data, we have identified a novel protein, CRTAP or Cartilage Associated Protein, that is representative of the Leprecanfamily of proteins recently reported to contain a conserved 2-oxoglutarate dioxygenase domain that is found in collagen 4-prolyl-hydroxylases, Hypoxic Inducible Factor (HIF) 4-prolyl-hydoxylases (PDHs), and lysyl hydroxylases (PLODs). Moreover, Leprecan or P3H1 has collagen 3-prolyl-hydroxylase activity in vitro implicating this family of genes as the long sought after PSH's. By combining human and mouse genetic, and proteomic approaches, we show (see Preliminary Studies C.2.) that loss of Crtap in mice causes an osteochondrodysplasia characterized by short stature, kyphosis, and severe osteoporosis. Moreover, this phenotype is biochemically associated with conversion of the single 3-hydroxy- proline to proline in the triple helical domain of types I and II collagen. CRTAP can bind P3H1 and is required for P3H activity in vivo. Finally, we found that loss of CRTAP is associatedwith recessive osteogenesis imperfecta types VII and ll/lll in humans. These data raise important questions that we will address in our Specific Aims. 1) Are the phenotypic features of Crtap loss of function due solely to loss of 3-prolyl- hydroxylation of fibrillar collagens and are there redundant functions with P3H1? 2) What are the consequences of 3-Hyp loss in cartilage and bone on cellular differentiation and function, and collagen biosynthesis? 3)What is the full human clinical spectrum associated with loss of 3-prolyl-hydroxylation of fibrillar collagens? By combining mouse and human studies, this proposal will interact directly with Projects I, II, and the Protein Biochemistry Core to answer these questions.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
5P01HD022657-23
Application #
7840364
Study Section
Pediatrics Subcommittee (CHHD)
Project Start
Project End
Budget Start
2009-05-01
Budget End
2010-04-30
Support Year
23
Fiscal Year
2009
Total Cost
$305,284
Indirect Cost
Name
Cedars-Sinai Medical Center
Department
Type
DUNS #
075307785
City
Los Angeles
State
CA
Country
United States
Zip Code
90048
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Rajagopal, Abbhirami; Homan, Erica P; Joeng, Kyu Sang et al. (2016) Restoration of the serum level of SERPINF1 does not correct the bone phenotype in Serpinf1 null mice. Mol Genet Metab 117:378-82
Xue, Yuan; Schoser, Benedikt; Rao, Aliz R et al. (2016) Exome Sequencing Identified a Splice Site Mutation in FHL1 that Causes Uruguay Syndrome, an X-Linked Disorder With Skeletal Muscle Hypertrophy and Premature Cardiac Death. Circ Cardiovasc Genet 9:130-5
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Hudson, David M; Joeng, Kyu Sang; Werther, Rachel et al. (2015) Post-translationally abnormal collagens of prolyl 3-hydroxylase-2 null mice offer a pathobiological mechanism for the high myopia linked to human LEPREL1 mutations. J Biol Chem 290:8613-22
Chen, Shan; Grover, Monica; Sibai, Tarek et al. (2015) Losartan increases bone mass and accelerates chondrocyte hypertrophy in developing skeleton. Mol Genet Metab 115:53-60
Weinstein, Michael M; Tompson, Stuart W; Chen, Yuqing et al. (2014) Mice expressing mutant Trpv4 recapitulate the human TRPV4 disorders. J Bone Miner Res 29:1815-1822
Joeng, Kyu Sang; Lee, Yi-Chien; Jiang, Ming-Ming et al. (2014) The swaying mouse as a model of osteogenesis imperfecta caused by WNT1 mutations. Hum Mol Genet 23:4035-42
Campeau, Philippe M; Kasperaviciute, Dalia; Lu, James T et al. (2014) The genetic basis of DOORS syndrome: an exome-sequencing study. Lancet Neurol 13:44-58

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