title: 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.
authors.affiliation: Division of Hematology/Oncology and Cancer Biology Program, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA. taraki@uhnres.utoronto.c
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Araki
authors.forename: Gordon
authors.initials: G
authors.lastname: Chan
authors.forename: Susan
authors.initials: S
authors.lastname: Newbigging
authors.forename: Lily
authors.initials: L
authors.lastname: Morikawa
authors.forename: Roderick T
authors.initials: RT
authors.lastname: Bronson
authors.forename: Benjamin G
authors.initials: BG
authors.lastname: Neel
mesh_terms: D000483:Alleles; D000818:Animals; D054089:Endocardial Cushions / Q000201:enzymology / Q000473:pathology; D004699:Endocardium / Q000201:enzymology* / Q000473:pathology*; D004789:Enzyme Activation; D055879:Gene Knock-In Techniques; D006330:Heart Defects, Congenital / Q000201:enzymology* / Q000473:pathology; D006351:Heart Valves / Q000002:abnormalities / Q000196:embryology / Q000201:enzymology; D008648:Mesoderm / Q000201:enzymology* / Q000473:pathology*; D051379:Mice; D009154:Mutation / Q000235:genetics; D009634:Noonan Syndrome / Q000201:enzymology*; D038081:Organogenesis; D010641:Phenotype; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism
chemical_list: D051057:Proto-Oncogene Proteins c-akt; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C516725:Ptpn11 protein, mouse