This application is designed to provide the candidate with support to continue his development as an independent physician-scientist with sufficient protected time to pursue his research in gene discovery and to provide mentorship to trainees. The candidate is Professor of Pediatrics and Human Genetics at the Mount Sinai School of Medicine. He is a board-certified pediatric cardiologist with expertise in the genetics of cardiovascular disease. His molecular genetics laboratory studies two autosomal dominant disorders with heart defects for which he has identified disease genes. Char syndrome, which has a phenotype that includes patent ductus arteriosus, is caused by transcription factor AP-2beta dominant-negative mutations. Noonan syndrome (NS), a pleiomorphic disorder with various cardiovascular abnormalities, is caused by gain-of-function defects in PTPN11, which encodes the protein tyrosine phosphatase SHP-2. The candidate has also discovered that similar PTPN11 mutations underlie other disease phenotypes, including certain myeloid disorders. In the proposed research, the candidate intends to test the hypotheses that PTPN11 mutations are associated with NS, with CHD other than pulmonic stenosis, as well as with non-syndromic CHD. NS cohorts with other anatomic subtypes and cohorts of subjects with only certain forms of CHD will be assembled and genotyped. The candidate expects that PTPN11 mutations causing sporadic CHD will be relatively milder and will be incompletely penetrant. It is also hypothesized that PTPN11 mutations alter phosphotyrosyl-binding domains cause NS by prolonging activation of SHP-2, that specific SHP-2 mutants causing LEOPARD syndrome will have greater gain-of-function than observed among classic NS mutants, and that mutations causing isolated CHD will result in less gain-of-function. To test these ideas, mutant SHP-2 proteins will be expressed in eukaryotic cells and tested for phosphatase activity, docking, as well as mitogen-activated protein kinase activity. The candidate hypothesizes that other genes altering the RAS-MAP kinase pathway also cause NS. He will document this through studies of signal transduction in skin fibroblasts derived from NS patients with and without PTPN11 mutations. Next, a candidate gene approach will be used to identify additional NS gene(s). This will be coupled with the use of human multiplex NS kindreds without PTPN11 mutations.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Midcareer Investigator Award in Patient-Oriented Research (K24)
Project #
2K24HD001294-06
Application #
6770877
Study Section
Pediatrics Subcommittee (CHHD)
Program Officer
Javois, Lorette Claire
Project Start
1999-05-12
Project End
2009-04-30
Budget Start
2004-05-01
Budget End
2005-04-30
Support Year
6
Fiscal Year
2004
Total Cost
$145,913
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
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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
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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
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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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