This Core resource to a program-project is focused on defining inborn protein defects that cause osteochondrodysplasia syndromes. We are determining the protein consequences at the molecular level of mutations in genes that cause defects in cartilage structure. This Protein Biochemistry Core actively collaborates in parallel with all projects by providing analytical data from specialized methods, including protein mass spectrometry, applied to tissue samples, purified proteins and cell-culture products. Both luman material from the International Skeletal Dysplasias Registry and mouse tissue and cellular products rom genetically engineered transgenic strains are being studied. Hypotheses as to the nature and biochemical effects of mutations that cause abnormal skeletal development and adult function are integral to the overall goals and aims of all projects and cores. The focus of the Protein Biochemistry Core is to understand the downstream molecular effects of mutations, both new ones identified by human genetic inkage and mutational analysis, and established mutations still with key questions on their protein pathogenesis and created transgenic defects in mice. An example of the latter is the systemic collagen defect in crtap -/- mice. The clinical significance of core work includes direct benefits to families with the conditions under study through more specific diagnoses. In the long term, through an understanding of the effects of altered gene expression, rational approaches to therapy are possible.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
5P01HD022657-22
Application #
7618450
Study Section
Pediatrics Subcommittee (CHHD)
Project Start
Project End
Budget Start
2008-05-01
Budget End
2009-04-30
Support Year
22
Fiscal Year
2008
Total Cost
$171,193
Indirect Cost
Name
Cedars-Sinai Medical Center
Department
Type
DUNS #
075307785
City
Los Angeles
State
CA
Country
United States
Zip Code
90048
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
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
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
Lietman, Caressa D; Marom, Ronit; Munivez, Elda et al. (2015) A transgenic mouse model of OI type V supports a neomorphic mechanism of the IFITM5 mutation. J Bone Miner Res 30:489-98
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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