This application is designed to provide the Principal Investigator with support to continue his development as an independent physician- scientist with sufficient protected time to pursue his research in gene discovery and provide mentorship to trainees. Dr. Gelb is an Associate Professor of Pediatrics and Human Genetics at the Mount Sinai School of Medicine. Clinically, he is a board certified pediatric cardiologist with expertise in the genetics of cardiovascular diseases. he directs a molecular genetics laboratory which investigates Mendelian and complex traits. The principal focus of his laboratory has been the study of pycnodysostosis (Pycno), an osteosclerotic bone dysplasia. Using a positional cloning approach, Dr. Gelb first established the Pycno critical region at chromosome 1q21 by linkage analysis, and then identified the disease gene as achtepsin K, a lysosomal cysteine protease. He has completed linkage studies for other Mendelian traits, including another osteosclerotic bone disorder, Kenny-Caffey syndrome (KCS). In the proposed research, the Principal Investigator intends to elucidate the critical role of Cathepsin K mutations will identified and then over expressed in Pichia pastoris. Mutant enzyme proteins will be characterized biochemically and the results compared OT the structural perturbations predicted by molecular modeling. In order to facilitate genotype-phenotype correlations as well as to better characterize this disorder, abnormalities in bone metabolism will be assessed in Pycnopatients using non-invasive markers, and the degree of cortical bone thickening and medullary narrowing documented by MRI. To understand the growth hormone (GH) deficiency associated with pycno, provocative testing of GH secretion and other pituitary functions will be pursued , and the anatomic status of the pituitary gland will be evaluated by MRI. Pycno osteoclast-like cells, generated in vitro from peripheral blood mononuclear cells, will be assessed functionally using a bone pit formation assay. Generalize inhibitors of cysteine cathepsins and metalloproteases will be used to document the nature of the residual proteolytic activity in Pycno. Transcript levels of known cysteine cathepsins will be assessed to detect upregulation of related proteases. Novel cysteine cathepsins with potential role in bone resorption will be sought from cathepsin K-deficient osteoclasts. Finally, studies will be initiated to identify the KCS gene which appears to have a central role in bone metabolism and calcium homeostasis. The KCS critical region will be refined by developing novel polymorphic markers and recruiting additional KCS families. Positional candidate genes, either known or from ESTs, will be scanned for mutations. Thereafter novel genes will be cloned from genomic clones spanning the KCS critical region. The Principal Investigator~s research career development will be supported with protected research time, dedicated laboratory space, Departmental and Institutational core facilities, as well as by the superb intellectual environment at Mount Sinai. he also will serve as a mentor for high quality M.D. and M.D./Ph.D. trainees who will be supported by NIH-funded training programs in his Departments and institution.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Midcareer Investigator Award in Patient-Oriented Research (K24)
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Special Emphasis Panel (ZHD1-DRG-A (07))
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Javois, Lorette Claire
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Mount Sinai School of Medicine
Schools of Medicine
New York
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Sarkozy, Anna; Carta, Claudio; Moretti, Sonia et al. (2009) Germline BRAF mutations in Noonan, LEOPARD, and cardiofaciocutaneous syndromes: molecular diversity and associated phenotypic spectrum. Hum Mutat 30:695-702
Oishi, Kimihiko; Zhang, Hui; Gault, William J et al. (2009) Phosphatase-defective LEOPARD syndrome mutations in PTPN11 gene have gain-of-function effects during Drosophila development. Hum Mol Genet 18:193-201
Cordeddu, Viviana; Di Schiavi, Elia; Pennacchio, Len A et al. (2009) Mutation of SHOC2 promotes aberrant protein N-myristoylation and causes Noonan-like syndrome with loose anagen hair. Nat Genet 41:1022-6
Lee, K A; Williams, B; Roza, K et al. (2009) PTPN11 analysis for the prenatal diagnosis of Noonan syndrome in fetuses with abnormal ultrasound findings. Clin Genet 75:190-4
Pandit, Bhaswati; Sarkozy, Anna; Pennacchio, Len A et al. (2007) Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. Nat Genet 39:1007-12
Tartaglia, Marco; Pennacchio, Len A; Zhao, Chen et al. (2007) Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome. Nat Genet 39:75-9
Xue, Jin; Zhou, Dan; Yao, Hang et al. (2007) Novel functional interaction between Na+/H+ exchanger 1 and tyrosine phosphatase SHP-2. Am J Physiol Regul Integr Comp Physiol 292:R2406-16
Weismann, Constance G; Gelb, Bruce D (2007) The genetics of congenital heart disease: a review of recent developments. Curr Opin Cardiol 22:200-6
Zampino, Giuseppe; Pantaleoni, Francesca; Carta, Claudio et al. (2007) Diversity, parental germline origin, and phenotypic spectrum of de novo HRAS missense changes in Costello syndrome. Hum Mutat 28:265-72
Tartaglia, Marco; Martinelli, Simone; Stella, Lorenzo et al. (2006) Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease. Am J Hum Genet 78:279-90

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