Journal
NATURE MEDICINE
Volume 10, Issue 8, Pages 849-857Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nm1084
Keywords
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Funding
- NCI NIH HHS [T32CA81156, R01 CA49152] Funding Source: Medline
- NHLBI NIH HHS [HL61475, T32HL007915, R01 HL62974] Funding Source: Medline
- NIDDK NIH HHS [DK66600, R01 DK64730, P01 DK50654, DK 64399] Funding Source: Medline
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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 similar to50% 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 (similar to 50%) have short stature, craniofacial abnormalities similar to those in Noonan syndrome, and myeloproliferative disease. Severely affected Ptpn11(D61G/+) embryos (similar to50%) 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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