The Skeletal Dysplasias

Rimoin, David L.

Abstract

The skeletal dysplasias are a heterogeneous group of disorders which result in disproportionate short stature and/or skeletal deformities. Although they have long been considered to be generalized disorders of endochondral and/or membraneous ossification, the extent of their heterogeneity has only recently been recognized and little is known concerning their pathogenesis. This project is directed toward a multidisciplinary investigation of the clinical, genetic, morphological and biochemical characteristics of the skeletal dysplasias.
The specific aims of this proposal will be: a) definition of the clinical, radiographic and genetic heterogeneity of the skeletal dysplasias; b) definition of the natural history, growth characteristics and complications of each of these disorders; c) delineation of the dynamics of craniofacial growth and development in each of these disorders; d) elucidation of the histological, histochemical, and ultrastructural characteristics of chondro-osseous tissue in each of these diseases; e) detailed analysis of the collagen composition of normal human fetal and postnatal cartilage; f) elucidation of the basic biochemical defects in each of these diseases by means of biochemical analysis of cartilage and metabolic studies of cultured chondrocytes; g) identification and investigation of specific animal models of the human chondrodystrophies; h) establishment of an International Registry of Dysplastic Skeletal Tissues. This program is divided into three separate grant proposals: 1) Clinical and Morphological studies, which will attempt to delineate the clinical and radiographic characteristics of these disorders, study the morphology and ultrastructure of their chondro-osseous tissue and identify and investigate specific animal models of these human disorders; 2) Collagen Polymorphism of Human Cartilage which will attempt to characterize the new varieties of collagen found in human cartilage and investigate their distribution and age related changes; and 3) Biochemical Studies of the Chondrodystrophies, which will attempt to define the molecular defects of chondrodystrophic cartilage components and characterize each of these aberrations.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
• Type: Research Program Projects (P01)
• Project #: 5P01HD022657-05
• Application #: 3097087
• Study Section: Maternal and Child Health Research Committee (HDMC)
• Project Start: 1986-12-01
• Project End: 1991-11-30
• Budget Start: 1990-12-01
• Budget End: 1991-11-30
• Support Year: 5
• Fiscal Year: 1991

Institution

• Name: Cedars-Sinai Medical Center
• DUNS #: 075307785
• City: Los Angeles
• State: CA
• Country: United States
• Zip Code: 90048

Publications

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