期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2014
卷号：111
期号：46
页码：16395-16400
DOI：10.1073/pnas.1418126111
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceNoonan syndrome (NS) is a developmental disorder caused by germ-line mutations in various components of the RAS signaling pathway. The pathophysiological mechanisms underlying the clinical manifestations in NS patients and the basis for the observed phenotypic variability are poorly understood. To date, mouse models carrying mutations in Protein Tyrosine Phosphatase Non-Receptor type 11 (Ptpn11), Son of Sevenless homolog 1 (Sos1), and Raf1 loci have been described. The new model described here, induced by K-RasV14I expression, recapitulates most of the NS features including small size, craniofacial dysmorphism, cardiac defects, and myeloproliferative disorders, highly reminiscent of juvenile myelomonocytic leukemia. These mice should help us understand better the phenotypic variations of NS and serve as a preclinical tool to test forthcoming therapies based on the design of novel inhibitors of the RAS pathway. Noonan syndrome (NS) is an autosomal dominant genetic disorder characterized by short stature, craniofacial dysmorphism, and congenital heart defects. NS also is associated with a risk for developing myeloproliferative disorders (MPD), including juvenile myelomonocytic leukemia (JMML). Mutations responsible for NS occur in at least 11 different loci including KRAS. Here we describe a mouse model for NS induced by K-RasV14I, a recurrent KRAS mutation in NS patients. K-RasV14I-mutant mice displayed multiple NS-associated developmental defects such as growth delay, craniofacial dysmorphia, cardiac defects, and hematologic abnormalities including a severe form of MPD that resembles human JMML. Homozygous animals had perinatal lethality whose penetrance varied with genetic background. Exposure of pregnant mothers to a MEK inhibitor rescued perinatal lethality and prevented craniofacial dysmorphia and cardiac defects. However, Mek inhibition was not sufficient to correct these defects when mice were treated after weaning. Interestingly, Mek inhibition did not correct the neoplastic MPD characteristic of these mutant mice, regardless of the timing at which the mice were treated, thus suggesting that MPD is driven by additional signaling pathways. These genetically engineered K-RasV14I-mutant mice offer an experimental tool for studying the molecular mechanisms underlying the clinical manifestations of NS. Perhaps more importantly, they should be useful as a preclinical model to test new therapies aimed at preventing or ameliorating those deficits associated with this syndrome.
