syndromes caused by mutations in either genes Disruptions of the RAS Signaling Network in Noonan's Syndrome Autosomal dominant gain-of-function mutations in PTPN11, encoding the protein tyrosine phosphatase SHP2, cause Noonan's syndrome, characterized by pulmonary stenosis, hypertrophic cardiomyopathy, and occasional atrioventricular valvar defects.77 Most recently, hypomorphic mutations in SOS1, an essential RAS guanine nucleotide-exchange factor (Ras-Gef), was shown to enhance RAS-ERK activation, and this can account for as high as one-fifth of the cases of Noonan's syndrome not explained by PTPN11 mutations.78,79 Recent evidence implicates epidermal growth factor signaling as an important regulator of late valvar remodeling Loss or attenuation of EGFR/ErbB1 signaling results in preferential hypercellularity of arterial but not atrioventricular valves.80 The hyperplastic arterial valvar phenotype is augmented when crossed to mice heterozygous for a null mutation in Ptpnl1.81 Deletion of the EGF ligand, heparin-binding epidermal growth factor, results in increased size of the endocardial cushions and ridges, along with the size and proliferation of cells in both the arterial and atrioventricular valvar leaflets.82,83 Nonsyndromic Mutations Mutations of NKX2-5 Cause Septation and Other Defects Mutations in the NKX2-5 gene cause defects similar to those caused by mutations of TBX5, namely deficiencies of atrial and ventricular septation, problems with conduction, hypoplasia of the left heart, and other anomalies such as tetralogy of Fallot or Ebstein's malformation.15,84–86 Mutations were originally identified in two families with very distinctive clinical features, namely progressive atrioventricular block in the setting of interatrial communications Subsequent studies showed that this unusual combination was not the only type of lesion that could be caused by the mutations Indeed, mutations in NKX2-5 were identified in several additional families that had some members presenting with an interatrial communication and atrioventricular block, but others with ventricular septal defects in isolation, Ebstein's malformation, and tetralogy of Fallot (Fig 4.2).84 These results were extended to sporadic cases, which in addition to several cases of interatrial communication within the oval fossa and tetralogy of Fallot, included rare sporadic cases of common arterial trunk, double-outlet right ventricle, congenitally corrected transposition, interrupted aortic arch, hypoplastic left heart syndrome, and aortic coarctation.86 This was perhaps not surprising to developmental biologists, who would expect a broad set of defects based on the pan-cardiac expression of the Nkx2-5 gene in the mouse, but it showed with definitive clarity that a single defined mutation could result in a wide range of clinically and anatomically unrelated defects This finding went a long way to explain the considerable difficulties in identifying familial inheritance of congenital cardiac malformations FIG 4.2 NKX2-5 mutations cause a variety of inherited congenital cardiac malformations Four family trees are shown, each representing a discrete mutation in NKX2-5 that, when inherited, is associated with a range of defects, including atrioventricular block (AV block), atrial septal defects (ASD), ventricular septal defects (VSD), and tricuspid valvar abnormality (TV abnormality) Circles represent females, squares represent males Roman numerals indicate generations within a family (Modified from Benson DW, Silberbach GM, Kavanaugh-McHugh A, et al Mutations in the cardiac transcription factor NKX2.5 affect diverse cardiac developmental pathways J Clin Invest 1999;104:1567–1573.) As with mutations of TBX5, a broad range of mutations have been identified in the NKX2-5 gene, which is made up of two rather compact exons Functional analysis of these mutations has determined that, for the most part, mutations of NKX2-5 result in a loss of activity for the gene, whether it be due to the production of a truncated protein, or one that cannot activate transcription by itself, or one that does not allow the gene to interact with its partner proteins such as TBX5 and GATA4.87,88 The biochemical basis of the differential expressivity of the various NKX2-5 mutations therefore has not been elucidated, and we are left once again with the potential for genetic modifiers as the modulating factors The progressive nature of the atrioventricular block in some patients with mutations of NKX2-5 was an important clue about one of its unexpected roles in the heart From a clinical standpoint, this discovery suggests that patients with the familial form of atrial septal defect should be followed longitudinally to check for the appearance of problems with atrioventricular conduction even after surgical correction of the septal defect Indeed, studies in the mouse have suggested that a primary defect in the conduction system is at the root of these problems with conduction, and that additionally the loss of Nkx2-5 might lead to cardiomyopathy unrelated to the structural defects or the abnormalities in the conduction system.89 Mutations of GATA4 Cause Problems With Septation Families have now been identified with problems in septation as a their sole phenotype Genetic mapping in two unrelated families with interatrial and interventricular communications have identified mutations in GATA4 (Fig 4.3).16 These mutations were predicted to result in a partial loss of function of the gene, and also predicted impaired interaction with Tbx5, thus linking the function of these two transcription factors to septation of the atrial and ventricular chambers Mutations in GATA4 have also been identified in a few