Here, we report on the identification of five different PTPN11 missense changes affecting residues Leu<sup>261</sup> , Leu<sup>262</sup> , and Arg<sup>265</sup> in 16 unrelated individuals with clinical diagnosis of NS or with features suggestive for this disorder, specifying a novel disease-causing mutation cluster.
We describe an 8-year-old girl who had Noonan syndrome involving a PTPN11 mutation, hypertrophic cardiomyopathy, main pulmonary artery dilation, and aortic root dilation.
Our results document a strict correlation between the identity of the lesion and disease and demonstrate that NS-causative mutations have less potency for promoting SHP-2 gain of function than do leukemia-associated ones.
In addition, these fly models can be used for sensitized screens to identify novel interacting genes as well as for high-throughput screening of therapeutic compounds for NS and PTPN11-related cancers.
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.