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      Noonan Syndrome: Genetics and Responsiveness to Growth Hormone Therapy

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          Background: The autosomal-dominant Noonan syndrome (MIM 163950) is characterized by short stature, heart defects, characteristic facial dysmorphic features and other major and minor anomalies. Its incidence has been estimated to be 1 in 1,000 to 2,500 live births. Familial cases are frequent. Methods and Results: Recently, molecular data have suggested that deregulation of signaling through the Ras-mitogen-activated protein kinase (Ras-MAPK) pathway was the main molecular basis of Noonan syndrome. The frequently detected upstream defects of this pathway are gain-of-function mutations of PTPN11, which are associated with a mild form of growth hormone (GH) resistance and insulin-like growth factor I (IGF-I) deficiency, presumably due to interference with the Janus kinase 2 and signal transducer and activator of transcription 5b (JAK2-STAT) signaling of the GH receptor. Present data suggest reduced GH responsiveness in these cases. Conclusions: Downstream defects of the Ras-MAPK pathway (like K-ras mutations) do not affect the JAK2-STAT pathway, and therefore response to GH therapy is likely to be better in these cases.

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          Most cited references 7

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          Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome.

          Noonan syndrome (MIM 163950) is an autosomal dominant disorder characterized by dysmorphic facial features, proportionate short stature and heart disease (most commonly pulmonic stenosis and hypertrophic cardiomyopathy). Webbed neck, chest deformity, cryptorchidism, mental retardation and bleeding diatheses also are frequently associated with this disease. This syndrome is relatively common, with an estimated incidence of 1 in 1,000-2,500 live births. It has been mapped to a 5-cM region (NS1) [corrected] on chromosome 12q24.1, and genetic heterogeneity has also been documented. Here we show that missense mutations in PTPN11 (MIM 176876)-a gene encoding the nonreceptor protein tyrosine phosphatase SHP-2, which contains two Src homology 2 (SH2) domains-cause Noonan syndrome and account for more than 50% of the cases that we examined. All PTPN11 missense mutations cluster in interacting portions of the amino N-SH2 domain and the phosphotyrosine phosphatase domains, which are involved in switching the protein between its inactive and active conformations. An energetics-based structural analysis of two N-SH2 mutants indicates that in these mutants there may be a significant shift of the equilibrium favoring the active conformation. This implies that they are gain-of-function changes and that the pathogenesis of Noonan syndrome arises from excessive SHP-2 activity.
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            The 'Shp'ing news: SH2 domain-containing tyrosine phosphatases in cell signaling.

            Src homology-2 (SH2) domain-containing phosphatases (Shps) are a small, highly conserved subfamily of protein-tyrosine phosphatases, members of which are present in both vertebrates and invertebrates. The mechanism of regulation of Shps by ligand binding is now well understood. Much is also known about the normal signaling pathways regulated by each Shp and the consequences of Shp deficiency. Recent studies have identified mutations in human Shp2 as the cause of the inherited disorder Noonan syndrome. Shp2 mutations might also contribute to the pathogenesis of some leukemias. In addition, Shp2 might be a key virulence determinant for the important human pathogen Helicobacter pylori. Despite these efforts, however, the key targets of each Shp have remained elusive. Identifying these substrates remains a major challenge for future research.
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              Germline KRAS mutations cause Noonan syndrome.

              Noonan syndrome (MIM 163950) is characterized by short stature, facial dysmorphism and cardiac defects. Heterozygous mutations in PTPN11, which encodes SHP-2, cause approximately 50% of cases of Noonan syndrome. The SHP-2 phosphatase relays signals from activated receptor complexes to downstream effectors, including Ras. We discovered de novo germline KRAS mutations that introduce V14I, T58I or D153V amino acid substitutions in five individuals with Noonan syndrome and a P34R alteration in a individual with cardio-facio-cutaneous syndrome (MIM 115150), which has overlapping features with Noonan syndrome. Recombinant V14I and T58I K-Ras proteins show defective intrinsic GTP hydrolysis and impaired responsiveness to GTPase activating proteins, render primary hematopoietic progenitors hypersensitive to growth factors and deregulate signal transduction in a cell lineage-specific manner. These studies establish germline KRAS mutations as a cause of human disease and infer that the constellation of developmental abnormalities seen in Noonan syndrome spectrum is, in large part, due to hyperactive Ras.

                Author and article information

                Horm Res Paediatr
                Hormone Research in Paediatrics
                S. Karger AG
                February 2007
                15 February 2007
                : 67
                : Suppl 1
                : 45-49
                Pediatric Endocrinology Section, University Children’s Hospital, Tübingen, Germany
                97552 Horm Res 2007;67:45–49
                © 2007 S. Karger AG, Basel

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                Page count
                Figures: 4, Tables: 1, References: 10, Pages: 5
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