Noonan syndrome cardiac defects are caused by PTPN11 acting in endocardium to enhance endocardial-mesenchymal transformation

摘要: Noonan syndrome (NS), the most common single-gene cause of congenital heart disease, is an autosomal dominant disorder that also features proportionate short stature, facial abnormalities, and increased risk myeloproliferative disease. Germline-activating mutations in PTPN11, which encodes protein tyrosine phosphatase SHP2, about half NS cases; other causative alleles include KRAS, SOS1, RAF1 mutants. We showed previously knock-in mice bearing mutant Ptpn11(D61G) on a mixed 129S4/SvJae X C57BL6/J background exhibit all major features, including variety cardiac defects, with variable penetrance. However, cellular molecular mechanisms underlying defects whether genetic and/or specific mutation contribute to phenotype remained unclear. Here, using inducible approach, we show result from Shp2 expression endocardium, not myocardium or neural crest. Furthermore, penetrance affected by Ptpn11 allele. Finally, ex vivo assays pharmacological approaches mutants valve increasing Erk MAPK activation, probably downstream ErbB family receptor kinases, extending interval during endocardial cells undergo endocardial-mesenchymal transformation. Our data provide mechanistic underpinning for this disorder.