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

Toshiyuki Araki, Gordon Chan, Susan Newbigging, Lily Morikawa, Roderickt Bronson, Benjamin G. Neel

Research output: Contribution to journalArticlepeer-review

101 Scopus citations

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-activat- ing 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.

Original languageEnglish
Pages (from-to)4736-4741
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number12
DOIs
StatePublished - 24 Mar 2009
Externally publishedYes

Keywords

  • Cardiac development
  • Cardiac valves
  • Human disease
  • Signal transduction protein tyrosine phosphatase

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