Noonan syndrome is a common human autosomal dominant birth defect, characterized by short stature, facial abnormalities, heart defects and possibly increased risk of leukemia. Mutations of Ptpn11 (also known as Shp2), which encodes the protein-tyrosine phosphatase Shp2, occur in ∼50% of individuals with Noonan syndrome, but their molecular, cellular and developmental effects, and the relationship between Noonan syndrome and leukemia, are unclear. We generated mice expressing the Noonan syndrome–associated mutant D61G. When homozygous, the D61G mutant is embryonic lethal, whereas heterozygotes have decreased viability. Surviving Ptpn11D61G/+ embryos (∼50%) have short stature, craniofacial abnormalities similar to those in Noonan syndrome, and myeloproliferative disease. Severely affected Ptpn11D61G/+ embryos (∼50%) have multiple cardiac defects similar to those in mice lacking the Ras-GAP protein neurofibromin. Their endocardial cushions have increased Erk activation, but Erk hyperactivation is cell and pathway specific. Our results clarify the relationship between Noonan syndrome and leukemia and show that a single Ptpn11 gain-of-function mutation evokes all major features of Noonan syndrome by acting on multiple developmental lineages in a gene dosage–dependent and pathway-selective manner.
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We thank C.J. Rosen and J. Burgess for measuring IGF-I levels in serum and W. Pu for helpful discussions. This work was supported by US National Institutes of Health (NIH) R01 CA49152 and DK66600 and a Translational Research Grant from the Leukemia and Lymphoma Society (to B.G.N.), NIH R01 HL62974 and HL61475 (to J.A.E.), N.I.H. P01 DK50654 (to B.G.N., D.G.G. and J.L.K.) and NIH R01 DK64730 (to I.R.W.). Flow cytometric studies were partially supported by Digestive Disease Research and Development Center grant NIH DK 64399. D.G.G. is an Investigator of the Howard Hughes Medical Institute. T. A. and M.G.M. were supported by fellowships from The Leukemia and Lymphoma Society. L.P. was supported by NIH training grant T32CA81156 and F.A.I. by NIH training grant T32HL007915.
B.G.N. is a member of the Scientific Advisory Board and a Consultant for Ceptyr, Inc. However, the work described in this manuscript was not supported by Ceptyr or any other pharmaceutical company. The other authors have no potentially competing financial interests to declare.
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