Noonan syndrome (MIM163950) is a clinically recognizable and genetically heterogeneous disorder. The common denominator of the various genetic alterations found in patients with Noonan syndrome and related disorders is that they cause dysregulation of RAS-MAPK signaling. Even if strict clinical criteria are applied, the molecular genetic lesion currently remains unidentified in about 10-20% of cases, thus suggesting additional genes for Noonan syndrome.
An international research collaboration has recently led to the discovery of NRAS mutations in 4 unrelated patients out of a large cohort of over 900 individuals negative for previously known mutations with a phenotype fitting or suggestive of Noonan syndrome (Cirstea et al., Nat Genet 2010). A few additional cases have been observed since then. The current data suggest that NRAS mutations account for less than 1% of cases with Noonan syndrome. The phenotype associated with NRAS mutations appears to have nothing specific and falls into the clinical category of Noonan syndrome with a relatively mild clinical expression in some of the mutation carriers. Although the number of mutation-positive cases is still too low to define valid genotype-phenotype correlations, it is notable that the typical congenital heart defects, such as pulmonary stenosis, hypertrophic cardiomyopathy and septal defects, were only observed in one third of these patients.
Three Noonan syndrome-associated NRAS mutations. I24N, T50I, and G60E, have been published, so far. Similar to KRAS, NRAS germline mutations are not identical to those commonly observed as somatic lesions in cancer. They have been shown to cause RAS overactivation. The precise mechanisms by which specific mutant NRAS proteins cause developmental anomalies typical of Noonan syndrome are still poorly understood.
Full list of authors:
Ion C Cirstea, Kerstin Kutsche, Radovan Dvorsky, Lothar Gremer, Claudio Carta, Denise Horn, Amy E Roberts, Francesca Lepri, Torsten Merbitz-Zahradnik, Rainer König, Christian P Kratz, Francesca Pantaleoni, Maria L Dentici, Victoria A Joshi, Raju S Kucherlapati, Laura Mazzanti, Stefan Mundlos, Michael A Patton, Margherita Cirillo Silengo, Cesare Rossi, Giuseppe Zampino, Cristina Digilio, Liborio Stuppia, Eva Seemanova, Len A Pennacchio, Bruce D Gelb, Bruno Dallapiccola, Alfred Wittinghofer, Mohammad R Ahmadian, Marco Tartaglia & Martin Zenker
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