Noonan syndrome: lessons learned from genetically modified mouse models.

Noonan syndrome is a RASopathy that results from activating mutations in different members of the RAS/MAPK signaling pathway. At least eleven members of this pathway have been found mutated, PTPN11 being the most frequently mutated gene affecting about 50% of the patients, followed by SOS1 (10%), RAF1 (10%) and KRAS (5%). Recently, even more infrequent mutations have been newly identified by next generation sequencing. This spectrum of mutations leads to a broad variety of clinical symptoms such as cardiopathies, short stature, facial dysmorphia and neurocognitive impairment. The genetic variability of this syndrome makes it difficult to establish a genotype-phenotype correlation, which will greatly help in the clinical management of the patients. Areas covered: Studies performed with different genetically engineered mouse models (GEMMs) developed up to date. Expert commentary: GEMMs have helped us understand the role of some genes and the effect of the different mutations in the development of the syndrome. However, few models have been developed and more characterization of the existing ones should be performed to learn about the impact of the different modifiers in the phenotypes, the potential cancer risk in patients, as well as preventative and therapeutic strategies.