Abstract 196: Adult-onset Cardiac Hypertrophy In LEOPARD Syndrome Is Caused By Both Cell Autonomous And Non-autonomous Effects That Occur During Development

Loss of function mutations in PTPN11 , the gene encoding the protein tyrosine phosphatase SHP2, cause LEOPARD Syndrome (LS), an autosomal dominant disorder with multiple cardiac defects, including hypertrophy. However, the mechanisms by which the LS mutants cause cardiac disease and regulate development remain unclear. Here, we utilized our inducible LS mouse model to determine whether LS mutations affect onset of cardiac hypertrophy via aberrant regulation of developmental processes. We examined hearts from wildtype (WT) or ubiquitously-expressing heterozygous LS (LS/+) and homozygous LS (LS/LS) embryos. As compared to WT, both LS/+ and LS/LS developing hearts showed diminished trabeculation, valvular hyperplasia and ventricular septal defects. In addition, LS/LS embryos had dextraposition of the aorta, leading to embryonic lethality. Gene expression analysis revealed that LS mutant hearts had decreased Foxp1/Fgf and Notch1/EphB2 signaling, suggesting perturbation of the reciprocal cross-talk between the developing endocardium and myocardium To assess this directly and to determine the in-vivo effects of lineage-specific LS expression during development, we generated, endothelial (Tie2)-, myocardial (Nkx2.5)- and neural crest (Wnt1)- specific LS/+ expressing mice. Surprisingly, the majority of LS cardiac defects, including the adult-onset cardiac hypertrophy, were recapitulated by expression of endocardial-specific LS alone, suggesting a functional necessity for the endocardium in hypertrophy of the heart. Moreover, though myocardial-specific expression of LS showed only minor developmental effects, these mice still recapitulated the adult-onset cardiac hypertrophy. Interestingly, no cardiac abnormalities were observed in the neural crest-specific expressing LS mice. Taken together, our data indicate that the LS mutations affect both cell autonomous and non-autonomous pathways necessary for the reciprocal cross-talk between endocardium and myocardium, and, importantly, that the adult-onset hypertrophy in LS is caused by aberrant signaling effects that occur during cardiac development.

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