The skeletal dysplasias (SDs) are a heterogeneous group of over 370 disorders of cartilage and bone affecting about 1 in 2,000. This project is aimed at defining the clinical, genetic, prenatal, pathologic, molecular, and pathophysiologic.features of these disorders to assist in understanding their causes and provide better information and clinical care to patients and families.
Specific aims i nclude: 1. To improve the characterization of the SDs: Using the large number of cases collected, we will continue our long-standing effort to improve the definition of the clinical, genetic, radiographic, and morphologic heterogeneity and variability of the SDs. We will define novel disorders, and improve the definition of the acrodysplasias, bent bone dysplasias, and thoraco-laryngo-pelvic dysplasia. We will test the hypothesis that flexion-extension MRI studies with measurements of cerebrospinal and venous flow will aid n defining the need for surgery in patients with ACH, an area of current controversy. 2. To define the prenatal presentation of the SDs and improve prenatal diagnosis: Many of the SDs, both lethal and nonlethal, have evidence of skeletal abnormalities in the prenatal period. We hypothesize that by employing 2D and 3D prenatal ultrasound (UTZ) and then correlating the findings to the fetal or newborn radiographic findings will lead to improved UTZ parameters for the prenatal diagnosis of these disorders. We will objectively determine UTZ parameters that best predict lethality in the immediate neonatal period, establish prenatal ultrasound measurements for brachydactyly in distinct osteochondrodysplasias, and determine differentiating ultrasound features for one group of commonly occurring group of disorders, the bent bone dysplasias. 3. To determine phenotype-genotype correlations in the SDs: Comparing the clinical phenotype with molecular and biochemical defects has allowed us to define the range of phenotypic variability of disorders, link pathophysiologically related disorders, and uncover heterogeneity. Due to their frequency and interest in their underlying pathogenic pathways, the program project team has chosen to study the short-rib polydactyly disorders and asphyxiating thoracic dysplasia, the brachyolmias, and autosomal recessive osteogenesis imperfecta types II and III. We will also continue studies begun in the previous cycle, including defining the characteristics of ACH and hypochondroplasia (HCH) with and without mutations in FGFR3, and Engelmann disease with and without TGF-_1 mutations. We further propose to test the hypothesis that Burton dysplasia and some of the cases of unclassified bent bone dysplasias are due to mutations in the perlecan gene. We will test the hypothesis that diaphanospondylodysostosis (DSD) is caused by mutations in the Pax1 gene.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Program Projects (P01)
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Pediatrics Subcommittee (CHHD)
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Cedars-Sinai Medical Center
Los Angeles
United States
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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
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
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
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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