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      Expanding the Genetic Spectrum of Noonan Syndrome

      case-report
      Hormone Research in Paediatrics
      S. Karger AG
      Noonan syndrome, Ras–MAP kinase signalling pathway, Pathogenesis

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          Abstract

          Background: The autosomal-dominant Noonan syndrome (MIM 163950) is characterized by short stature, typical facial dysmorphology and heart defects. Noonan syndrome is genetically heterogeneous. Over the last few years, germline mutations in four genes have been found in people with clinical signs of Noonan syndrome, accounting for approximately 65% of cases. All four genes encode proteins involved in the Ras–mitogen-activated protein kinase pathway and result in upregulation of this pathway. Recently, more data on final height after long-term growth hormone (GH) therapy has become available that shows its effectiveness in increasing final height for individuals with Noonan syndrome. Conclusions: The genetics underlying Noonan syndrome has been partially clarified over the last 5 years and further findings will undoubtedly be reported in the next few years. GH therapy has been used to treat patients with Noonan syndrome for approximately 15 years and is effective in improving adult height in affected children.

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          Most cited references10

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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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            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.
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              Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome.

              Noonan syndrome is a developmental disorder characterized by short stature, facial dysmorphia, congenital heart defects and skeletal anomalies. Increased RAS-mitogen-activated protein kinase (MAPK) signaling due to PTPN11 and KRAS mutations causes 50% of cases of Noonan syndrome. Here, we report that 22 of 129 individuals with Noonan syndrome without PTPN11 or KRAS mutation have missense mutations in SOS1, which encodes a RAS-specific guanine nucleotide exchange factor. SOS1 mutations cluster at codons encoding residues implicated in the maintenance of SOS1 in its autoinhibited form. In addition, ectopic expression of two Noonan syndrome-associated mutants induces enhanced RAS and ERK activation. The phenotype associated with SOS1 defects lies within the Noonan syndrome spectrum but is distinctive, with a high prevalence of ectodermal abnormalities but generally normal development and linear growth. Our findings implicate gain-of-function mutations in a RAS guanine nucleotide exchange factor in disease for the first time and define a new mechanism by which upregulation of the RAS pathway can profoundly change human development.
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                Author and article information

                Journal
                HRE
                Horm Res Paediatr
                10.1159/issn.1663-2818
                Hormone Research in Paediatrics
                S. Karger AG
                978-3-8055-8475-3
                978-3-8055-8476-0
                1663-2818
                1663-2826
                2007
                December 2007
                10 December 2007
                : 68
                : Suppl 5
                : 24-27
                Affiliations
                Metabolic and Endocrine Disorders, Radboud University Medical Centre, Nijmegen, The Netherlands
                Article
                110468 Horm Res 2007;68:24–27
                10.1159/000110468
                18174700
                53e2fc33-59f0-42f3-9c4b-4b636d491a36
                © 2007 S. Karger AG, Basel

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                History
                Page count
                Tables: 1, References: 15, Pages: 4
                Categories
                Hot Topics: Combined Session 1

                Endocrinology & Diabetes,Neurology,Nutrition & Dietetics,Sexual medicine,Internal medicine,Pharmacology & Pharmaceutical medicine
                Ras–MAP kinase signalling pathway,Noonan syndrome,Pathogenesis

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