Nature Medicine
10, 849 - 857 (2004)
Published online: 25 July 2004; | doi:10.1038/nm1084
Mouse model of Noonan syndrome reveals cell type− and gene dosage−dependent effects of Ptpn11 mutationToshiyuki Araki1, M Golam Mohi1, Fraz A Ismat2, Roderick T Bronson3, Ifor R Williams4, Jeffery L Kutok5, Wentian Yang1, Lily I Pao1, D Gary Gilliland6, Jonathan A Epstein7
& Benjamin G Neel11
Cancer Biology Program, Division of Hematology-Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, NRB1038, 330 Brookline Ave., Boston, Massachusetts 02215, USA. 2
Division of Cardiology, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA. 3
Rodent Histopathology Core, Harvard Medical School, Boston, MA 02115, USA. 4
Department of Pathology, Emory University, Atlanta, Georgia 30322, USA. 5
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA. 6
Division of Hematology-Oncology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA. 7
Department of Medicine, Cardiology Division, University of Pennsylvania Health System, Philadelphia, Pennsylvania 19104, USA.
Correspondence should be addressed to Toshiyuki Araki taraki@bidmc.harvard.eduNoonan 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 Ptpn11
D61G/+ embryos (50%) have short stature, craniofacial abnormalities similar to those in Noonan syndrome, and myeloproliferative disease. Severely affected Ptpn11
D61G/+ 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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