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-offunction 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.
SPECIFIC AIM 3 ’s hypothesis is that the Jak-Stat signaling pathway, which interacts with NS alleles in fruit fly development, is perturbed during cardiogenesis in NS. We will characterize the roles of Jak-Stat signaling during normal and perturbed cardiogenesis in wild type and Ptpn11D61G mice, respectively, using immunological and genetic approaches. Taken as a whole, the studies proposed in this application will delineate the range of genes that cause NS and LS when mutated as well as provide insights into the effects of their mutant protein products at the biochemical, cellular, and organismal levels. The insights gained will be leveraged in the future to elucidate genetic causes of non-syndromic cardiac defects as well as to develop novel therapeutic strategies to ameliorate these phenotypes.

Public Health Relevance

Genetic defects altering the RAS-mitogen activated protein kinase (MAPK) cascade, a fundamental signal transduction pathway, have been linked to the pathogenesis of cancer for some time but were only recently found to cause Noonan syndrome (NS) and related developmental disorders. Here, we propose to discover additional NS genes and to elucidate disease pathogenesis. This work will advance our understanding of NS and related disorders and can lead to insights into diseases such as cancer and hypertrophic cardiomyopathy.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Cardiovascular Differentiation and Development Study Section (CDD)
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Schramm, Charlene A
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Icahn School of Medicine at Mount Sinai
Schools of Medicine
New York
United States
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Talukdar, Husain A; Foroughi Asl, Hassan; Jain, Rajeev K et al. (2016) Cross-Tissue Regulatory Gene Networks in Coronary Artery Disease. Cell Syst 2:196-208
Miller, Clint L; Pjanic, Milos; Wang, Ting et al. (2016) Integrative functional genomics identifies regulatory mechanisms at coronary artery disease loci. Nat Commun 7:12092
Franzén, Oscar; Ermel, Raili; Cohain, Ariella et al. (2016) Cardiometabolic risk loci share downstream cis- and trans-gene regulation across tissues and diseases. Science 353:827-30
Sanderson, Saskia C; Linderman, Michael D; Suckiel, Sabrina A et al. (2016) Motivations, concerns and preferences of personal genome sequencing research participants: Baseline findings from the HealthSeq project. Eur J Hum Genet 24:14-20
Stevenson, David A; Schill, Lisa; Schoyer, Lisa et al. (2016) The Fourth International Symposium on Genetic Disorders of the Ras/MAPK pathway. Am J Med Genet A 170:1959-66
Quintero-Rivera, Fabiola; Xi, Qiongchao J; Keppler-Noreuil, Kim M et al. (2015) MATR3 disruption in human and mouse associated with bicuspid aortic valve, aortic coarctation and patent ductus arteriosus. Hum Mol Genet 24:2375-89
Mulero-Navarro, Sonia; Sevilla, Ana; Roman, Angel C et al. (2015) Myeloid Dysregulation in a Human Induced Pluripotent Stem Cell Model of PTPN11-Associated Juvenile Myelomonocytic Leukemia. Cell Rep 13:504-515
Cordeddu, Viviana; Yin, Jiani C; Gunnarsson, Cecilia et al. (2015) Activating Mutations Affecting the Dbl Homology Domain of SOS2 Cause Noonan Syndrome. Hum Mutat 36:1080-7
Gelb, Bruce D; Roberts, Amy E; Tartaglia, Marco (2015) Cardiomyopathies in Noonan syndrome and the other RASopathies. Prog Pediatr Cardiol 39:13-19
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

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