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

Abstract

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

SH2 Domain–Containing Phosphatase-2 Is a Novel Antifibrotic Regulator in Pulmonary Fibrosis

“…Global SHP2 deficiency is embryonically lethal in mice, due to major developmental defects (33,36). Support for a potential role for SHP2 in lung fibrosis has emerged from observations that targeted genetic ablations of SHP2 in AECs (19) or macrophages (20) are profibrotic.…”

Next-generation sequencing identifies rare variants associated with Noonan syndrome

“…We did not find such a correlation, perhaps because our cohort was relatively small. Alternatively, increased HCM incidence might correlate with RIT1 mutations only in Asian NS patients; notably, strain background can strongly affect the penetrance of NS phenotypes in mouse models (29). Aoki et al also did not see consistent hyperactivation of ERK in heterologous cells expressing NSassociated RIT1 mutants.…”

Developmental SHP2 dysfunction underlies cardiac hypertrophy in Noonan syndrome with multiple lentigines

“…However, despite abnormal craniofacial effects indicative of neural crest origins, we did not observe any obvious aberrant cardiac phenotypes, suggesting that LOF of SHP2 activity does not affect neural crest-derived development of the heart. Similarly, murine neural crest-specific expression of NS does not give a cardiac phenotype (50). Indeed, hypertrophy.…”

“…In contrast, GOF of SHP2 in NS, which also leads to increased valve size, facilitates EndoMT during valvulogenesis through upregulation of ERK signaling (50). The importance of ERK activity in mediating abnormal valve development in NS was further demonstrated when transgenic SHP2 Q79R mice were crossed to homozygous ERK1 deleted mice, rescuing the endocardial cushion defects (53).…”