Vissers L et al. Heterozygous germline mutations in A2ML1 are associated with a disorder clinically related to Noonan syndrome. European Journal of Human Genetics (2015) 23, 317-324.
For a quarter of patients clinically diagnosed with Noonan syndrome, the molecular cause cannot be identified. Through exome sequencing in a case-parent trio, followed by targeted resequencing in 155 patients and functional confirmation of pathogenicity in zebrafish, Vissers et al. identify mutations in A2ML1 as a cause of a Noonan-like disorder with a wide spectrum of severity.
The authors note that A2ML1 is a protease inhibitor that binds to the LRP1 receptor, which in turn directly interacts with CBL and is also an upstream activator of the MAPK/ERK cascade. They therefore speculate that A2ML1 may function upstream of the signalling pathways involved in Noonan syndrome. Perplexingly, expression of A2ML1 mutations did not lead to detectable RAS/MAPK activation in vitro. The authors suggest that this may either be a function of the cell types used in their study, or a true reflection of the fact that the effects of A2ML1 mutations are not mediated by the MAPK/ERK cascade.
This study adds one more gene to the list of possible causes of Noonan syndrome. As the first report of mutations in a gene encoding an extracellular cofactor causing a Noonan-like syndrome, it also suggests a direction for further studies of the complex molecular pathophysiology underlying this disorder.