1. Developmental SHP2 dysfunction underlies cardiac hypertrophy in Noonan syndrome with multiple lentigines
- Author
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Lauriol, Jessica, Cabrera, Janel R., Roy, Ashbeel, Keith, Kimberly, Hough, Sara M., Damilano, Federico, Wang, Bonnie, Segarra, Gabriel C., Flessa, Meaghan E., Miller, Lauren E., Das, Saumya, Bronson, Roderick, Lee, Kyu-Ho, and Kontaridis, Maria I.
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Gene expression -- Health aspects ,Noonan syndrome -- Genetic aspects -- Development and progression ,Phosphatases -- Health aspects ,Cellular signal transduction -- Genetic aspects -- Health aspects ,Health care industry - Abstract
Hypertrophic cardiomyopathy is a common cause of mortality in congenital heart disease (CHD). Many gene abnormalities are associated with cardiac hypertrophy, but their function in cardiac development is not well understood. Loss-of- function mutations in PTPN11, which encodes the protein tyrosine phosphatase (PTP) SHP2, are implicated in CHD and cause Noonan syndrome with multiple lentigines (NSML), a condition that often presents with cardiac hypertrophic defects. Here, we found that NSML-associated hypertrophy stems from aberrant signaling mechanisms originating in developing endocardium. Trabeculation and valvular hyperplasia were diminished in hearts of embryonic mice expressing a human NSML-associated variant of SHP2, and these defects were recapitulated in mice expressing NSML-associated SHP2 specifically in endothelial, but not myocardial or neural crest, cells. In contrast, mice with myocardial- but not endothelial-specific NSML SHP2 expression developed ventricular septal defects, suggesting that NSML-associated mutations have both cell-autonomous and nonautonomous functions in cardiac development. However, only endothelial-specific expression of NSML-associated SHP2 induced adult-onset cardiac hypertrophy. Further, embryos expressing the NSML-associated SHP2 mutation exhibited aberrant AKT activity and decreased downstream forkhead box P1 (FOXP1)/FGF and NOTCH1/EPHB2 signaling, indicating that SHP2 is required for regulating reciprocal crosstalk between developing endocardium and myocardium. Together, our data provide functional and disease-based evidence that aberrant SHP2 signaling during cardiac development leads to CHD and adult-onset heart hypertrophy., Introduction With a prevalence of approximately 1:100 children and over 500,000 adult cases reported in the United States alone, congenital heart disease (CHD) remains the most common birth defect worldwide [...]
- Published
- 2016
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