Noonan and LEOPARD syndromes (NS and LS) are autosomal dominant traits with features that include congenital heart disease (CHD), short stature, dysmorphism, and mental retardation;LS also includes lentigines. We have shown that PTPN11 missense mutations cause nearly 50% of NS and engender gain-of- function on its protein, the protein tyrosine phosphatase SHP-2. Loss-of-function PTPN11 mutations cause LS. Recently, we found that KRAS mutations cause 1% of NS. SHP-2 and KRAS play roles in RAS-mitogen activated protein kinase (MAPK) signaling.
SPECIFIC AIM 1 will test the hypothesis that the unknown NS genes encode proteins in RAS-MAPK signaling. Candidate genes will be resequenced in a high throughput fashion with a large cohort of NS subjects without PTPN11 or KRAS mutation. Biochemical and cell culture approaches will be used to test the effects of mutations on novel NS genes.
In SPECIFIC AIM 2, we hypothesize that SHP-2 mutants cause LEOPARD syndrome through gain-of-function effects on development despite their reduced phosphatase activity and that NS-associated KRAS mutations alter signaling more profoundly than do NS PTPN11 defects. To test these ideas, we will generate transgenic fruit flies inducibly expressing homologous NS and LS mutant proteins. Their phenotypes and genetic interactions will be characterized. Further, we hypothesize that genes interacting genetically with the Egfr-related wing phenotype from the existing NS fruit fly model will identify novel aspects of signal transduction as well as new NS disease genes. A sensitized screen will be performed to identify genes that suppress or enhance that wing phenotype.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Cardiovascular Differentiation and Development Study Section (CDD)
Program Officer
Schramm, Charlene A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Icahn School of Medicine at Mount Sinai
Schools of Medicine
New York
United States
Zip Code
Dhandapany, Perundurai S; Razzaque, Md Abdur; Muthusami, Uthiralingam et al. (2014) RAF1 mutations in childhood-onset dilated cardiomyopathy. Nat Genet 46:635-9
Cornwall, James W; Green, Robert S; Nielsen, James C et al. (2014) Frequency of aortic dilation in Noonan syndrome. Am J Cardiol 113:368-71
Flex, Elisabetta; Jaiswal, Mamta; Pantaleoni, Francesca et al. (2014) Activating mutations in RRAS underlie a phenotype within the RASopathy spectrum and contribute to leukaemogenesis. Hum Mol Genet 23:4315-27
Edwards, Jonathan J; Martinelli, Simone; Pannone, Luca et al. (2014) A PTPN11 allele encoding a catalytically impaired SHP2 protein in a patient with a Noonan syndrome phenotype. Am J Med Genet A 164A:2351-5
Roberts, Amy E; Allanson, Judith E; Tartaglia, Marco et al. (2013) Noonan syndrome. Lancet 381:333-42
Lepri, Francesca; De Luca, Alessandro; Stella, Lorenzo et al. (2011) SOS1 mutations in Noonan syndrome: molecular spectrum, structural insights on pathogenic effects, and genotype-phenotype correlations. Hum Mutat 32:760-72
Gelb, Bruce D; Tartaglia, Marco (2011) RAS signaling pathway mutations and hypertrophic cardiomyopathy: getting into and out of the thick of it. J Clin Invest 121:844-7
Tartaglia, Marco; Gelb, Bruce D; Zenker, Martin (2011) Noonan syndrome and clinically related disorders. Best Pract Res Clin Endocrinol Metab 25:161-79
Dhandapany, Perundurai S; Fabris, Frank; Tonk, Rahul et al. (2011) Cyclosporine attenuates cardiomyocyte hypertrophy induced by RAF1 mutants in Noonan and LEOPARD syndromes. J Mol Cell Cardiol 51:4-15
Tartaglia, Marco; Gelb, Bruce D (2010) Disorders of dysregulated signal traffic through the RAS-MAPK pathway: phenotypic spectrum and molecular mechanisms. Ann N Y Acad Sci 1214:99-121

Showing the most recent 10 out of 36 publications