Molecular genetics of Noonan syndrome

Noonan syndrome (NS) is a genetically heterogeneous disorder that can result from mutations in the PTPN11, SOS1, KRAS, RAF1 and MEK1 genes, which encode transducers participating in the RAS-MAP kinase (MAPK) signaling pathway. The disorder is generally transmitted as an autosomal dominant trait, although many cases result from de novo mutations. Defects in the PTPN11 gene, which encodes the Src homology 2 (SH2) containing protein tyrosine phosphatase SHP-2, account for approximately 50% of cases. The more than 60 mutations that have been reported are almost all missense changes, and promote upregulation of protein function. Two additional distinct classes of missense PTPN11 mutations have been identified as somatic lesions in hematological malignancies and germline defects in LEOPARD syndrome (LS), which is clinically related to NS. While the former are generally more activating compared to the NS-causing mutations, the latter cause loss of catalytic activity of the phosphatase. Defects in the KRAS proto-oncogene account for roughly 2% of NS cases and engender gain of function in RAS signaling through reduced KRAS GTPase activity or increased GDP/GTP dissociation rate. As documented for PTPN11, the distributions of affected residues and amino acid substitutions in NS and cancer appear to be largely mutually exclusive. Missense mutations in SOS1 occur in approximately 10% of affected individuals. SOS1 is a RAS-specific guanine nucleotide exchange factor that catalyzes the release of GDP from RAS, facilitating the conversion of its inactive GDP-bound form to active GTP-bound RAS. NS-causing SOS1 mutations are activating and affect residues placed in domains that stabilize the catalytically autoinhibited conformation of the protein. Finally, a small percentage of NS results from missense mutations in the RAF1 and MEK1 genes. RAF1 is a member of a small family of serine-threonine kinases, which are effectors of RAS that activate the dual specificity kinases MEK1 and MEK2. Activated MEK proteins, in turn, activate the MAPKs, ERK1 and ERK2. RAF1 gene mutations are observed in about 5% of NS cases and affect residues clustered in three regions of the protein with amino acid substitutions within the consensus 14-3- 3 recognition sequence around Ser²⁵⁹ accounting for 75% of the mutations. Since 14-3-3 binding at residue Ser ²⁵⁹ stabilizes RAF1's catalytically inactive conformation and impairs its translocation to the plasma membrane, mutations affecting this motif promote increased RAF1 activity. Additional studies are required to fully understand the functional consequences of mutations affecting residues placed within the other two mutational hot spots within the activation segment region of the kinase domain and at the C-terminus. RAF1 gene mutations also account for approximately 3% of subjects with LS, and possibly a relevant fraction of pediatric cases with isolated hypertrophic cardiomyopathy. A single missense MEK1 mutation has been reported in two unrelated subjects with sporadic NS. MEK1 gene mutations are estimated to account for less than 2% of affected individuals. No data on the effect of the predicted amino acid change on MEK1 function and MAPK signaling is currently available.