Materiały źródłowe

• #1 Noonan Syndrome – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK532269/

  Noonan syndrome is a genetically inherited disease with heterogeneous, phenotypic manifestations. Gene mutations involve the RAAS/MAPK (mitogen-activated protein kinase) signaling pathway. […] The RAS/MAPK pathway mutation in Noonan syndrome classifies Noonan syndrome as RASopathy. RASopathies are genetic syndromes that involve germline mutations in the Ras/mitogen-activated protein kinase (MAPK) pathway. […] The most common mutation in Noonan syndrome occurs in the PTPN11 gene. A smaller portion of mutations occurs in SOS1, RAF1, and RIT1. Mutations in PTPN11 can be inherited, autosomal dominant, or occur de novo through sporadic mutation. The mutations involved in Noonan syndrome are considered a gain of function mutation, causing inappropriate prolongation of the RAS/MAPK signaling. The prolongation of the RAS/MAPK pathway gives way to the pleomorphic characteristics found in Noonan syndrome.

• #2 Noonan syndrome – Wikipedia

  https://en.wikipedia.org/wiki/Noonan_syndrome

  Noonan syndrome is a genetic disorder that may present with mildly unusual facial features, short height, congenital heart disease, bleeding problems, and skeletal malformations. […] A number of genetic mutations can result in Noonan syndrome. The condition may be inherited as an autosomal dominant condition or occur as a new mutation. Noonan syndrome is a type of RASopathy, the underlying mechanism for which involves attenuation of the RAS/MAPK cell signaling pathway. […] Mutations in the Ras/mitogen activated protein kinase signaling pathways are known to be responsible for about 70% of NS cases. […] Several genes are involved in the genetic etiology of NS, with the key ones being PTPN11 accounting for 50% of genetically diagnosed cases, SOS1 responsible for 10-13% of cases, and RAF1 or RIT1 – each contributing to an additional 5% of cases. Correlations between phenotype and genotype exist, and identifying the genetic cause can shed light on expected symptoms. For example, mutations in the PTPN11 gene are associated with an increased tendency for pulmonary stenosis or leukemia, while mutations in the SOS1 gene are linked to relatively normal development and stature compared to other NS cases. About 15-20% of NS cases remain genetically undiagnosed.

• #3 Noonan syndrome and RASopathies: Clinical features, diagnosis and management

  https://www.e-kjgm.org/journal/view.html?doi=10.5734/JGM.2019.16.1.1

  Noonan syndrome (NS) and NS-related disorders (cardio-facio-cutaneous syndrome, Costello syndrome, NS with multiple lentigines, or LEOPARD [lentigines, ECG conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation of growth and sensory neural deafness] syndrome) are collectively named as RASopathies. […] During past decades, molecular etiologies of RASopathies have been growingly discovered. The functional perturbations of the RAS-mitogen-activated protein kinase pathway are resulted from the mutation of more than 20 genes (PTPN11, SOS1, RAF1, SHOC2, BRAF, KRAS, NRAS, HRAS, MEK1, MEK2, CBL, SOS2, RIT, RRAS, RASA2, SPRY1, LZTR1, MAP3K8, MYST4, A2ML1, RRAS2). […] The molecular pathogenesis behind RASopathies is now increasingly understood. It is commonly resulted from gain of function of the RAS-MAPK signaling pathway. The MAPK signaling pathway plays a bio-functional role of growth factor-mediated cell proliferation, differentiation, and apoptosis.

• #4 Noonan Syndrome: Clinical Aspects and Molecular Pathogenesis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2858523/

  The RAS-MAPK cascade is activated in response to cytokine, hormone and growth factor stimulation, and is a major mediator of early and late developmental processes, including morphology determination, organogenesis, synaptic plasticity processes and growth. […] Thus far, 7 genes (PTPN11, SOS1, KRAS, RAF1, BRAF, SHOC2 and MEK1, alias MAP2K1) have been causally related to NS or closely related conditions, including LEOPARD syndrome and Noonan-like syndrome with loose anagen hair. […] PTPN11 was discovered as a major NS disease gene by using a positional candidacy approach in 2001. […] Based on those efforts, it has now been established that PTPN11 mutations account for approximately 50% of NS, and are more prevalent among subjects with pulmonary valve stenosis and short stature, and less common in individuals with HCM and/or severe cognitive deficits.

• #5 Noonan Syndrome: Clinical Aspects and Molecular Pathogenesis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2858523/

  Noonan syndrome (NS) is caused by mutations in the PTPN11, SOS1, KRAS, RAF1, BRAF and MEK1 (MAP2K1) genes, accounting for approximately 70% of affected individuals. […] SHP2 (encoded by PTPN11), SOS1, BRAF, RAF1 and MEK1 positively contribute to RAS-MAPK signaling, and possess complex autoinhibitory mechanisms that are impaired by mutations. […] Similarly, reduced GTPase activity or increased guanine nucleotide release underlie the aberrant signal flow through the MAPK cascade promoted by most KRAS mutations. […] These recent discoveries demonstrate that the substantial phenotypic variation characterizing NS and related conditions can be ascribed, in part, to the gene mutated and even the specific molecular lesion involved. […] NS is genetically heterogeneous, and, based upon the recent discoveries of the underlying disease genes, it can now be regarded as a disorder of upregulated RAS-MAPK signaling.

• #6 Research on the Pathogenesis of Cognitive and Neurofunctional Impairments in Patients with Noonan Syndrome: The Role of Rat Sarcoma–Mitogen Activated Protein Kinase Signaling Pathway Gene Disturbances

  https://www.mdpi.com/2073-4425/14/12/2173

  Germline pathogenic variants in genes encoding proteins in the RAS/MAPK signaling pathway (Rat Sarcoma–Mitogen Activated Protein Kinase) play an essential role in the pathogenesis of Noonan syndrome. […] Based on the current knowledge regarding the involvement of the RAS/MAPK pathway in brain development, including synaptic plasticity and neuronal functions, it is highly probable that cognitive deficits may be associated with mutations in particular genes, leading to the dysregulation of the RAS/MAPK pathway. […] The aim of our research project was to verify the hypothesized potential role of disturbances in the RAS/MAPK signaling cascade in the pathomechanism of cognitive impairments, as well as functional and structural brain abnormalities examined using region-based morphometry, DTI, and rs-fMRI in patients with molecularly confirmed Noonan syndrome.

• #7 Noonan syndrome: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/noonan-syndrome/

  Noonan syndrome is a condition that affects many areas of the body. […] The PTPN11, SOS1, RAF1, and RIT1 genes all provide instructions for making proteins that are important in the RAS/MAPK cell signaling pathway, which is needed for cell division and growth (proliferation), the process by which cells mature to carry out specific functions (differentiation), and cell movement (migration). Many of the mutations in the genes associated with Noonan syndrome cause the resulting protein to be turned on (active) longer than normal, rather than promptly switching on and off in response to cell signals. This prolonged activation alters normal RAS/MAPK signaling, which disrupts the regulation of cell growth and division, leading to the characteristic features of Noonan syndrome. […] Rarely, Noonan syndrome is associated with genes that are not involved in the RAS/MAPK cell signaling pathway. Researchers are working to determine how mutations in these genes can lead to the signs and symptoms of Noonan syndrome.

• #8 Noonan Syndrome: Clinical Aspects and Molecular Pathogenesis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2858523/

  The RAS-MAPK cascade is activated in response to cytokine, hormone and growth factor stimulation, and is a major mediator of early and late developmental processes, including morphology determination, organogenesis, synaptic plasticity processes and growth. […] Thus far, 7 genes (PTPN11, SOS1, KRAS, RAF1, BRAF, SHOC2 and MEK1, alias MAP2K1) have been causally related to NS or closely related conditions, including LEOPARD syndrome and Noonan-like syndrome with loose anagen hair. […] PTPN11 was discovered as a major NS disease gene by using a positional candidacy approach in 2001. […] Based on those efforts, it has now been established that PTPN11 mutations account for approximately 50% of NS, and are more prevalent among subjects with pulmonary valve stenosis and short stature, and less common in individuals with HCM and/or severe cognitive deficits.

• #9 Noonan Syndrome: Practice Essentials, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/947504-overview

  The pathophysiology of Noonan syndrome is not fully understood but is associated with mutations in genes that are part of the RAS/RAF/MEK/ERK signal transduction pathway, an important regulator of cell growth. Approximately 50% of patients have gene mutations in PTPN11, with SOS1 and RAF1 mutations identified in another 13% and 5-17% of patients, respectively. Mutations in KRAS, NRAS, BRAF, MAP2K1, MRAS, RASA2, RIT1, RRAS2, SOS2, and LZATR1 also have been identified. Several other genes that have been linked to a Noonan syndromelike phenotype have been recognized as well but have been found in a very small number of persons. […] A study by Barg et al indicated that platelet dysfunction and plasma coagulation factor deficiencies contribute to bleeding diathesis in Noonan syndrome. Of the 24 children in the study, platelet dysfunction was identified in 50%. Clotting factor deficiencies and von Willebrand disease were also identified. Thrombin generation parameters were significantly lower than those in controls, but thrombin generation results were not found to be significantly correlated with bleeding symptoms.

• #10 Noonan syndrome – UpToDate

  https://www.uptodate.com/contents/noonan-syndrome

  Noonan syndrome (NS) is a common autosomal-dominant condition that is associated with short stature and congenital heart disease (CHD), most often pulmonic stenosis. […] This topic reviews the epidemiology, genetics, pathophysiology, clinical manifestations, diagnosis, and management of NS. […] NS is nearly always an autosomal-dominant condition, and two-thirds of patients are the first affected person in their family due to a de novo pathogenic variant. Approximately 50 percent of patients have a pathogenic variant in protein tyrosine phosphatase, nonreceptor type 11 (PTPN11), with clustering of variants in specific codons. […] The genetic basis in the remainder of patients is usually a pathogenic variant in one of many other genes encoding a protein of the Ras-mitogen-activated protein kinase (Ras-MAPK) pathway.

• #11 Noonan syndrome

  https://dermnetnz.org/topics/noonan-syndrome

  Noonan syndrome is a common autosomal dominant disorder associated with mutations in the Ras/mitogenactivated protein kinase (MAPK) pathway and is one of a group of conditions that are collectively known as RASopathies. […] Noonan syndrome is caused by mutations in the genes associated with the Ras/MAPK cell-signalling pathway, which is required for normal cell division, proliferation, differentiation and migration. These mutations lead to the loss of regulation of cell growth and division. […] Mutations in the PTPN11 gene are implicated in over 50% of Noonan syndrome cases. Gene mutations in SOS1 are implicated in 10-15% of cases and mutations in the RAF1 gene and the RIT1 gene account for approximately 5% each. A number of other genes account for the rest. […] The genetic cause behind Noonan syndrome is unknown in up to 20% of cases.

• #12 Noonan syndrome | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-2-4

  Noonan Syndrome (NS) is characterised by short stature, typical facial dysmorphology and congenital heart defects. […] In approximately 50% of cases, the disease is caused by missense mutations in the PTPN11 gene on chromosome 12, resulting in a gain of function of the non-receptor protein tyrosine phosphatase SHP-2 protein. […] The mutations associated with NS result in a gain of function of SHP-2. […] Heterogeneous gain-of-function mutations in PTPN11 are found in almost half of the patients with clinically definite NS. […] The most frequent NS-causing PTPN11 mutation is an A-to-G transition at nucleotide 922. […] A genotype-phenotype correlation has also been identified between a C-to-T transition on nucleotide 218 (Thr73Ile) and a predisposition to a myeloproliferative disorder. […] Recently activating mutations in the KRAS gene, which is associated with the Ras pathway, were found as the causative dominant mutations in a few cases with NS. […] These findings establish hyperactive Ras as a cause of developmental abnormalities seen in NS.

• #13 NOONAN SYNDROME

  https://medicover-genetics.com/product/noonan-syndrome/

  Noonan syndrome is an autosomal dominant inherited disorder with a broad, variable spectrum of symptoms, including facial dysmorphia, short stature, chest deformities and heart defects. It belongs to a group of cardiovascular conditions known as RASopathies, and in 50% of cases is due to pathogenic variants in the PTPN11 gene. […] The PTPN11 gene, which codes for a cytoplasmic protein tyrosine phosphatase (SHP-2), is the gene mainly affected in Noonan syndrome. Pathogenic variants in the PTPN11 gene, which almost exclusively lead to amino acid exchanges, are the molecular cause in about 50% of all Noonan patients investigated so far. […] Pathogenic variants have currently been identified in several other genes, including the RASERK-MAP kinase signal transduction in Noonan syndrome. Mutations in the SOS1 (Son of Sevenless) gene were detected in up to 15% of Noonan patients who did not have a mutation in the PTPN11 gene. Pathogenic variants in the RAF1 gene could be identified in about 8% of Noonan patients. Almost all patients with RAF1 mutations show hypertrophic cardiomyopathy. Other genes include RIT1 (approximately 5% of patients) and KRAS (approximately 3% of patients), pathogenic variants here predominantly lead to severe phenotypes.

• #14 Noonan syndrome – Wikipedia

  https://en.wikipedia.org/wiki/Noonan_syndrome

  Noonan syndrome is a genetic disorder that may present with mildly unusual facial features, short height, congenital heart disease, bleeding problems, and skeletal malformations. […] A number of genetic mutations can result in Noonan syndrome. The condition may be inherited as an autosomal dominant condition or occur as a new mutation. Noonan syndrome is a type of RASopathy, the underlying mechanism for which involves attenuation of the RAS/MAPK cell signaling pathway. […] Mutations in the Ras/mitogen activated protein kinase signaling pathways are known to be responsible for about 70% of NS cases. […] Several genes are involved in the genetic etiology of NS, with the key ones being PTPN11 accounting for 50% of genetically diagnosed cases, SOS1 responsible for 10-13% of cases, and RAF1 or RIT1 – each contributing to an additional 5% of cases. Correlations between phenotype and genotype exist, and identifying the genetic cause can shed light on expected symptoms. For example, mutations in the PTPN11 gene are associated with an increased tendency for pulmonary stenosis or leukemia, while mutations in the SOS1 gene are linked to relatively normal development and stature compared to other NS cases. About 15-20% of NS cases remain genetically undiagnosed.

• #15 Noonan Syndrome: Practice Essentials, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/947504-overview

  The pathophysiology of Noonan syndrome is not fully understood but is associated with mutations in genes that are part of the RAS/RAF/MEK/ERK signal transduction pathway, an important regulator of cell growth. Approximately 50% of patients have gene mutations in PTPN11, with SOS1 and RAF1 mutations identified in another 13% and 5-17% of patients, respectively. Mutations in KRAS, NRAS, BRAF, MAP2K1, MRAS, RASA2, RIT1, RRAS2, SOS2, and LZATR1 also have been identified. Several other genes that have been linked to a Noonan syndromelike phenotype have been recognized as well but have been found in a very small number of persons. […] A study by Barg et al indicated that platelet dysfunction and plasma coagulation factor deficiencies contribute to bleeding diathesis in Noonan syndrome. Of the 24 children in the study, platelet dysfunction was identified in 50%. Clotting factor deficiencies and von Willebrand disease were also identified. Thrombin generation parameters were significantly lower than those in controls, but thrombin generation results were not found to be significantly correlated with bleeding symptoms.

• #16 Noonan Syndrome: Practice Essentials, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/947504-overview

  The pathophysiology of Noonan syndrome is not fully understood but is associated with mutations in genes that are part of the RAS/RAF/MEK/ERK signal transduction pathway, an important regulator of cell growth. Approximately 50% of patients have gene mutations in PTPN11, with SOS1 and RAF1 mutations identified in another 13% and 5-17% of patients, respectively. Mutations in KRAS, NRAS, BRAF, MAP2K1, MRAS, RASA2, RIT1, RRAS2, SOS2, and LZATR1 also have been identified. Several other genes that have been linked to a Noonan syndromelike phenotype have been recognized as well but have been found in a very small number of persons. […] A study by Barg et al indicated that platelet dysfunction and plasma coagulation factor deficiencies contribute to bleeding diathesis in Noonan syndrome. Of the 24 children in the study, platelet dysfunction was identified in 50%. Clotting factor deficiencies and von Willebrand disease were also identified. Thrombin generation parameters were significantly lower than those in controls, but thrombin generation results were not found to be significantly correlated with bleeding symptoms.

• #17 Noonan syndrome – UpToDate

  https://www.uptodate.com/contents/noonan-syndrome

  Pathogenic variants in leucine zipper-like transcription regulator 1 (LZTR1) may underpin approximately 10 percent of NS, and these may show either autosomal-dominant or autosomal-recessive inheritance, with consequent implications for recurrence risk in future pregnancies in the family. […] Approximately 10 percent of patients tested do not have an identifiable pathogenic variant in any of the known genes, suggesting that additional genes may be involved.

• #18 Noonan syndrome – UpToDate

  https://www.uptodate.com/contents/noonan-syndrome

  Pathogenic variants in leucine zipper-like transcription regulator 1 (LZTR1) may underpin approximately 10 percent of NS, and these may show either autosomal-dominant or autosomal-recessive inheritance, with consequent implications for recurrence risk in future pregnancies in the family. […] Approximately 10 percent of patients tested do not have an identifiable pathogenic variant in any of the known genes, suggesting that additional genes may be involved.

• #19 Noonan syndrome – Wikipedia

  https://en.wikipedia.org/wiki/Noonan_syndrome

  Noonan syndrome is a genetic disorder that may present with mildly unusual facial features, short height, congenital heart disease, bleeding problems, and skeletal malformations. […] A number of genetic mutations can result in Noonan syndrome. The condition may be inherited as an autosomal dominant condition or occur as a new mutation. Noonan syndrome is a type of RASopathy, the underlying mechanism for which involves attenuation of the RAS/MAPK cell signaling pathway. […] Mutations in the Ras/mitogen activated protein kinase signaling pathways are known to be responsible for about 70% of NS cases. […] Several genes are involved in the genetic etiology of NS, with the key ones being PTPN11 accounting for 50% of genetically diagnosed cases, SOS1 responsible for 10-13% of cases, and RAF1 or RIT1 – each contributing to an additional 5% of cases. Correlations between phenotype and genotype exist, and identifying the genetic cause can shed light on expected symptoms. For example, mutations in the PTPN11 gene are associated with an increased tendency for pulmonary stenosis or leukemia, while mutations in the SOS1 gene are linked to relatively normal development and stature compared to other NS cases. About 15-20% of NS cases remain genetically undiagnosed.

• #20 Noonan syndrome pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Noonan_syndrome_pathophysiology

  Structurally, the SHP-2 protein has 2 important domains an SH2 and a catalytically active PTP domain whose interaction is defective in patients with PTPN11 mutations. The SH2 domain acts as a chaperon that covers the active site of PTP basally. Because of this interaction, SHP-2 is maintained auto-inhibited except when it is required to be functional. Most of the mutations in PTPN11 affect amino acid residues close to this interaction surface between those 2 domains. This suggests that the pathophysiology of Noonan syndrome involves a shift in the equilibrium between active and inactive SHP-2 toward the active form without any effect on the function of the protein itself.

• #21 Noonan Syndrome: Clinical Aspects and Molecular Pathogenesis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2858523/

  Most of the mutations affect residues involved in the N-SH2/PTP interdomain binding network that stabilizes SHP2 in its catalytically inactive conformation or are in close spatial proximity to them. […] A distinct class of PTPN11 mutations has been identified to underlie LEOPARD syndrome (LS; OMIM 151100). […] PTPN11 mutation screening on a relatively large number of children with NS and JMML has demonstrated the presence of germline mutations in the majority of cases, with one mutation rarely observed in NS, c.218CT (Thr73Ile), occurring in a large percentage of children. […] The association between this specific amino acid change and JMML in NS and the key-role of SHP2 in RAS signaling and hematopoiesis suggested that a distinct class of lesions in the gene, possibly acquired as a somatic event, might play a role in leukemogenesis.

• #22 Noonan syndrome pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Noonan_syndrome_pathophysiology

  Them most studied mutation leading to Noonan syndrome involves the N-SH2 domain of the SHP-2 protein involved in signal transduction as part of the RAS-MAP Kinase pathway. This mutation allows SHP-2 to become constitutively activated leading to an increase in downstream signaling and disruption of embryogenesis. […] The functional pathogenesis of Noonan syndrome has been mostly elaborated in the context of PTPN11 mutations. The PTPN11 gene codes for the SHP-2 protein, a cytoplasmic SH2 domain-containing protein tyrosine phosphatase that is ubiquitous in adult and embryonic tissues. Functionally, the SHP-2 protein acts as an intracellular signal transducer that has a particularily important role during development. It is mainly involved in mesodermal patterning and gastrulation during early embryogenesis but also plays a role in the formation of terminal and skeletal structures, semilunar valvulogenesis, and hematopoiesis. It has been shown that SHP-2 positively controls the activation of the RAS/MAPK cascade, the SRC family kinase, and IL-1/TNF-dependent NF-B activation.

• #23 Noonan syndrome pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Noonan_syndrome_pathophysiology

  Structurally, the SHP-2 protein has 2 important domains an SH2 and a catalytically active PTP domain whose interaction is defective in patients with PTPN11 mutations. The SH2 domain acts as a chaperon that covers the active site of PTP basally. Because of this interaction, SHP-2 is maintained auto-inhibited except when it is required to be functional. Most of the mutations in PTPN11 affect amino acid residues close to this interaction surface between those 2 domains. This suggests that the pathophysiology of Noonan syndrome involves a shift in the equilibrium between active and inactive SHP-2 toward the active form without any effect on the function of the protein itself.

• #24

  https://www.omim.org/entry/163950

  In more than 50% of patients with Noonan syndrome, Tartaglia et al. (2001) identified mutations in the PTPN11 gene (see, e.g., 176876.0001-176876.0003). All the PTPN11 missense mutations were clustered in the interacting portions of the amino N-SH2 (Src homology 2) domain and the phosphotyrosine phosphatase (PTP) domains, which are involved in switching the protein between its inactive and active conformations. An energetics-based structural analysis of 2 N-SH2 mutants indicated that in these cases there may be a significant shift of the equilibrium favoring the active conformation. The findings suggested that gain-of-function changes resulting in excessive SHP2 activity underlie the pathogenesis of Noonan syndrome. […] After germline mutations in PTPN11 (176876) were demonstrated in the Noonan syndrome, Tartaglia et al. (2003) investigated defects in PTPN11 in myeloid disorders including cases of juvenile myelomonocytic leukemia (JMML; 607785) in children with Noonan syndrome. Specific mutations in PTPN11 associated with isolated JMML occurred as somatic changes and had never been observed as germline defects, leading Tartaglia et al. (2003) to speculate that these molecular defects are stronger and associated with embryonic lethality. Conversely, most mutations in PTPN11 associated with Noonan syndrome, which were sufficient to perturb developmental processes, were not fully leukemogenic, suggesting a milder gain-of-function effect.

• #25 Noonan syndrome and RASopathies: Clinical features, diagnosis and management

  https://www.e-kjgm.org/journal/view.html?doi=10.5734/JGM.2019.16.1.1

  Noonan syndrome (NS) and NS-related disorders (cardio-facio-cutaneous syndrome, Costello syndrome, NS with multiple lentigines, or LEOPARD [lentigines, ECG conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation of growth and sensory neural deafness] syndrome) are collectively named as RASopathies. […] During past decades, molecular etiologies of RASopathies have been growingly discovered. The functional perturbations of the RAS-mitogen-activated protein kinase pathway are resulted from the mutation of more than 20 genes (PTPN11, SOS1, RAF1, SHOC2, BRAF, KRAS, NRAS, HRAS, MEK1, MEK2, CBL, SOS2, RIT, RRAS, RASA2, SPRY1, LZTR1, MAP3K8, MYST4, A2ML1, RRAS2). […] The molecular pathogenesis behind RASopathies is now increasingly understood. It is commonly resulted from gain of function of the RAS-MAPK signaling pathway. The MAPK signaling pathway plays a bio-functional role of growth factor-mediated cell proliferation, differentiation, and apoptosis.

• #26 Noonan Syndrome – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK532269/

  Noonan syndrome is a genetically inherited disease with heterogeneous, phenotypic manifestations. Gene mutations involve the RAAS/MAPK (mitogen-activated protein kinase) signaling pathway. […] The RAS/MAPK pathway mutation in Noonan syndrome classifies Noonan syndrome as RASopathy. RASopathies are genetic syndromes that involve germline mutations in the Ras/mitogen-activated protein kinase (MAPK) pathway. […] The most common mutation in Noonan syndrome occurs in the PTPN11 gene. A smaller portion of mutations occurs in SOS1, RAF1, and RIT1. Mutations in PTPN11 can be inherited, autosomal dominant, or occur de novo through sporadic mutation. The mutations involved in Noonan syndrome are considered a gain of function mutation, causing inappropriate prolongation of the RAS/MAPK signaling. The prolongation of the RAS/MAPK pathway gives way to the pleomorphic characteristics found in Noonan syndrome.

• #27 Noonan syndrome | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-2-4

  Noonan Syndrome (NS) is characterised by short stature, typical facial dysmorphology and congenital heart defects. […] In approximately 50% of cases, the disease is caused by missense mutations in the PTPN11 gene on chromosome 12, resulting in a gain of function of the non-receptor protein tyrosine phosphatase SHP-2 protein. […] The mutations associated with NS result in a gain of function of SHP-2. […] Heterogeneous gain-of-function mutations in PTPN11 are found in almost half of the patients with clinically definite NS. […] The most frequent NS-causing PTPN11 mutation is an A-to-G transition at nucleotide 922. […] A genotype-phenotype correlation has also been identified between a C-to-T transition on nucleotide 218 (Thr73Ile) and a predisposition to a myeloproliferative disorder. […] Recently activating mutations in the KRAS gene, which is associated with the Ras pathway, were found as the causative dominant mutations in a few cases with NS. […] These findings establish hyperactive Ras as a cause of developmental abnormalities seen in NS.

• #28 Molecular and clinical studies in 107 Noonan syndrome affected individuals with PTPN11 mutations | BMC Medical Genetics | Full Text

  https://bmcmedgenet.biomedcentral.com/articles/10.1186/s12881-020-0986-5

  Nearly all studies carried out to date on NS mutation testing have attempted genotype-phenotype correlation. However, the most consistent feature across studies has been that there exists a great deal of phenotypic variation even among patients with the same pathogenic variant. […] The most frequently occurring pathogenic variants in our cohort, c.922AG and c.923AG, both of which change the same amino acid (Asn308), were seen in 22 patients, including a three-generation-affected pedigree.

• #29 Molecular and clinical studies in 107 Noonan syndrome affected individuals with PTPN11 mutations | BMC Medical Genetics | Full Text

  https://bmcmedgenet.biomedcentral.com/articles/10.1186/s12881-020-0986-5

  Nearly all studies carried out to date on NS mutation testing have attempted genotype-phenotype correlation. However, the most consistent feature across studies has been that there exists a great deal of phenotypic variation even among patients with the same pathogenic variant. […] The most frequently occurring pathogenic variants in our cohort, c.922AG and c.923AG, both of which change the same amino acid (Asn308), were seen in 22 patients, including a three-generation-affected pedigree.

• #30 Noonan Syndrome: Clinical Aspects and Molecular Pathogenesis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2858523/

  Noonan syndrome (NS) is caused by mutations in the PTPN11, SOS1, KRAS, RAF1, BRAF and MEK1 (MAP2K1) genes, accounting for approximately 70% of affected individuals. […] SHP2 (encoded by PTPN11), SOS1, BRAF, RAF1 and MEK1 positively contribute to RAS-MAPK signaling, and possess complex autoinhibitory mechanisms that are impaired by mutations. […] Similarly, reduced GTPase activity or increased guanine nucleotide release underlie the aberrant signal flow through the MAPK cascade promoted by most KRAS mutations. […] These recent discoveries demonstrate that the substantial phenotypic variation characterizing NS and related conditions can be ascribed, in part, to the gene mutated and even the specific molecular lesion involved. […] NS is genetically heterogeneous, and, based upon the recent discoveries of the underlying disease genes, it can now be regarded as a disorder of upregulated RAS-MAPK signaling.

• #31 Mutation-Specific Mechanisms of Hyperactivation of Noonan Syndrome SOS Molecules Detected with Single-molecule Imaging in Living Cells | Scientific Reports

  https://www.nature.com/articles/s41598-017-14190-6

  Noonan syndrome (NS) is a congenital hereditary disorder associated with developmental and cardiac defects. Some patients with NS carry mutations in SOS, a guanine nucleotide exchange factor (GEF) for the small GTPase RAS. NS mutations have been identified not only in the GEF domain, but also in various domains of SOS, suggesting that multiple mechanisms disrupt SOS function. […] The association and dissociation kinetics between SOS tagged with a fluorescent protein and the living cell surface were observed in single molecules. All three mutants showed increased affinity for the plasma membrane, inducing excessive RAS signalling. However, the mechanisms by which their affinity was increased were specific to each mutant. Conformational disorder in the resting state, increased probability of a conformational change on the plasma membrane, and an increased association rate constant with the membrane receptor are the suggested mechanisms.

• #32 Mutation-Specific Mechanisms of Hyperactivation of Noonan Syndrome SOS Molecules Detected with Single-molecule Imaging in Living Cells | Scientific Reports

  https://www.nature.com/articles/s41598-017-14190-6

  Clarification of the pathological mechanism of each NS mutant in hyperactivating the RASMAPK pathway is crucial to establishing techniques for the rational treatment of NS. […] Mutations in the Cdc25 domain may directly increase the GEF activity of SOS, inducing the hyperactivation of the RASMAPK pathway. However, mutations in the other domains must affect RASMAPK activation through indirect mechanisms. […] The discovery of various genetic mutations in NS patients suggests that the common feature of NS (i.e., the excessive activation of the RASMAPK pathway) results from many molecular mechanisms. More than 30 different NS-related point mutations have been reported in the SOS molecule alone. […] A higher density of SOS on the cell surface simply increases the probability of it contacting the inactive form RAS, which is then activated by SOS.

• #33 Noonan syndrome and RASopathies: Clinical features, diagnosis and management

  https://www.e-kjgm.org/journal/view.html?doi=10.5734/JGM.2019.16.1.1

  The germ-line mutations enhancing the function of the RAS-MAPK pathway components are underlying molecular mechanism for the development of NS and NS-related disorders. […] The mutation spectrum of CS and NSML are unique, mostly found in HRAS and PTPN11 genes respectively. […] The functional alteration of the three variants were verified by exploring the downstream effectors in the RAS-MAPK pathway. […] The RAF1 activity is enhanced by GTP-bounded RAS, subsequently phosphorylating serine residues of MEK. […] The p.K170E mutation of SOS1 is located in the histone fold (HF) domain, where mutations were rarely reported. […] Despite extensive efforts utilizing single gene, targeted panel, and whole exome sequencing in order to discover responsible genes of RASopathies, around 20% of patients with RASopathies remain genetically undiagnosed.

• #34 RIT1: a novel gene associated with Noonan syndrome

  https://www.imrpress.com/journal/RN/63/8/10.33588/rn.6308.2016183

  Introduction: Noonan syndrome is the most frequent of the congenital group of malformation syndromes caused by germline mutations that encode components of the RAS/MAPK pathway, termed RASopathies, one of the most frequent congenital genetic disorders in the clinical practice. Recently RIT1 mutations have been reported in patients with Noonan syndrome. […] RIT1 shares homology with other RAS proteins and the expression of mutant alleles demonstrates a gain-of-function effect supporting a causative role in Noonan syndrome pathogenesis. Data suggest that the frequency of RIT1 mutations can be estimated as 3-5% in Noonan syndrome patients. These cases compared with Noonan patients harboring mutations in other genes are characterized by high frequency of prenatal abnormalities and hypertrophic cardiomyopathy, and lower frequencies of short stature and pectus abnormalities. We emphasize the importance of the novel identified genes in order to be included in the diagnostic panels.

• #35 Noonan Syndrome: Clinical Aspects and Molecular Pathogenesis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2858523/

  Noonan syndrome (NS) is caused by mutations in the PTPN11, SOS1, KRAS, RAF1, BRAF and MEK1 (MAP2K1) genes, accounting for approximately 70% of affected individuals. […] SHP2 (encoded by PTPN11), SOS1, BRAF, RAF1 and MEK1 positively contribute to RAS-MAPK signaling, and possess complex autoinhibitory mechanisms that are impaired by mutations. […] Similarly, reduced GTPase activity or increased guanine nucleotide release underlie the aberrant signal flow through the MAPK cascade promoted by most KRAS mutations. […] These recent discoveries demonstrate that the substantial phenotypic variation characterizing NS and related conditions can be ascribed, in part, to the gene mutated and even the specific molecular lesion involved. […] NS is genetically heterogeneous, and, based upon the recent discoveries of the underlying disease genes, it can now be regarded as a disorder of upregulated RAS-MAPK signaling.

• #36 Noonan Syndrome: Clinical Aspects and Molecular Pathogenesis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2858523/

  Noonan syndrome (NS) is caused by mutations in the PTPN11, SOS1, KRAS, RAF1, BRAF and MEK1 (MAP2K1) genes, accounting for approximately 70% of affected individuals. […] SHP2 (encoded by PTPN11), SOS1, BRAF, RAF1 and MEK1 positively contribute to RAS-MAPK signaling, and possess complex autoinhibitory mechanisms that are impaired by mutations. […] Similarly, reduced GTPase activity or increased guanine nucleotide release underlie the aberrant signal flow through the MAPK cascade promoted by most KRAS mutations. […] These recent discoveries demonstrate that the substantial phenotypic variation characterizing NS and related conditions can be ascribed, in part, to the gene mutated and even the specific molecular lesion involved. […] NS is genetically heterogeneous, and, based upon the recent discoveries of the underlying disease genes, it can now be regarded as a disorder of upregulated RAS-MAPK signaling.

• #37 Novel insights in Noonan syndrome

  https://oatext.com/novel-insights-in-noonan-syndrome.php

  Noonan syndrome is a genetic pathology due to sporadic or inherited mutations, with normal karyotype; most cases are transmitted in an autosomal dominant manner and for these reasons males and females are equally affected. […] As mentioned, pathogenetic mutations are part of RAS MAPK signal transduction pathway. In addition to PTPN11, that accounts for approximatively 50% of mutations, pathogenetic mutations have been demonstrated in SOS1, RAF1, KRAS, NRAS, SHOC2, CBL, BRAF, SOS2, RIT1, RRAS, RASA2, SPRY1, LZTR1, MAP3K8, MYST4, and A2ML1. […] PTPN11 mutations result in a gain of function of SHP-2. There are no phenotypic features exclusive to a specific genotype, anyway genotype-phenotype correlations may be useful since there are significant differences in the risk of various NS manifestations based on the causative gene.

• #38 Noonan Syndrome: Clinical Aspects and Molecular Pathogenesis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2858523/

  The RAS-MAPK cascade is activated in response to cytokine, hormone and growth factor stimulation, and is a major mediator of early and late developmental processes, including morphology determination, organogenesis, synaptic plasticity processes and growth. […] Thus far, 7 genes (PTPN11, SOS1, KRAS, RAF1, BRAF, SHOC2 and MEK1, alias MAP2K1) have been causally related to NS or closely related conditions, including LEOPARD syndrome and Noonan-like syndrome with loose anagen hair. […] PTPN11 was discovered as a major NS disease gene by using a positional candidacy approach in 2001. […] Based on those efforts, it has now been established that PTPN11 mutations account for approximately 50% of NS, and are more prevalent among subjects with pulmonary valve stenosis and short stature, and less common in individuals with HCM and/or severe cognitive deficits.

• #39 Molecular and clinical studies in 107 Noonan syndrome affected individuals with PTPN11 mutations | BMC Medical Genetics | Full Text

  https://bmcmedgenet.biomedcentral.com/articles/10.1186/s12881-020-0986-5

  Noonan syndrome (NS), an autosomal dominant developmental genetic disorder, is caused by germline mutations in genes associated with the RAS / mitogen-activated protein kinase (MAPK) pathway. In several studies PTPN11 is one of the genes with a significant number of pathogenic variants in NS-affected patients. Therefore, clinically diagnosed NS individuals are initially tested for pathogenic variants in PTPN11 gene to confirm the relationship before studying genotype-phenotype correlation. […] The most commonly identified pathogenic variants in this series were in exon 8 (c.922AG, c.923AG), observed in 22 of the affected. Congenital cardiac anomalies were present in 84% of the mutation-positive cohort, the majority being defects in the right side of the heart. […] Clinical features such as pulmonary stenosis (PS), short stature and thoracic deformities are more consistently associated with PTPN11 mutations than other clinical features.

• #40 Molecular and clinical studies in 107 Noonan syndrome affected individuals with PTPN11 mutations | BMC Medical Genetics | Full Text

  https://bmcmedgenet.biomedcentral.com/articles/10.1186/s12881-020-0986-5

  Noonan syndrome (NS), an autosomal dominant developmental genetic disorder, is caused by germline mutations in genes associated with the RAS / mitogen-activated protein kinase (MAPK) pathway. In several studies PTPN11 is one of the genes with a significant number of pathogenic variants in NS-affected patients. Therefore, clinically diagnosed NS individuals are initially tested for pathogenic variants in PTPN11 gene to confirm the relationship before studying genotype-phenotype correlation. […] The most commonly identified pathogenic variants in this series were in exon 8 (c.922AG, c.923AG), observed in 22 of the affected. Congenital cardiac anomalies were present in 84% of the mutation-positive cohort, the majority being defects in the right side of the heart. […] Clinical features such as pulmonary stenosis (PS), short stature and thoracic deformities are more consistently associated with PTPN11 mutations than other clinical features.

• #41 Molecular and clinical studies in 107 Noonan syndrome affected individuals with PTPN11 mutations | BMC Medical Genetics | Full Text

  https://bmcmedgenet.biomedcentral.com/articles/10.1186/s12881-020-0986-5

  The association of congenital heart defects in some studies is greater than 80% indicating that NS is the second syndrome after Down syndrome with respect to frequency of cardiac defects. […] The SH2 domains are responsible for the interaction with phosphotyrosine-containing activators which contain binding sites for the N-SH2 domain. The PTP domain includes four loops, namely the P loop, pY loop, WPD loop and Q loop, which together enclose the active site pocket and have specific roles in SHP2 activity. […] NS and Noonan syndrome with multiple lentigines (NSML, MIM *151100) are the result of a gain-of-function mutation in PTPN11. […] The absence of frameshift, nonsense or even splicing mutations in our cohort and in other similar studies implies that there is no haploinsufficiency in PTPN11 expression and that PTPN11 haploinsufficiency does not cause NS.

• #42 Noonan syndrome – Wikipedia

  https://en.wikipedia.org/wiki/Noonan_syndrome

  Noonan syndrome is a genetic disorder that may present with mildly unusual facial features, short height, congenital heart disease, bleeding problems, and skeletal malformations. […] A number of genetic mutations can result in Noonan syndrome. The condition may be inherited as an autosomal dominant condition or occur as a new mutation. Noonan syndrome is a type of RASopathy, the underlying mechanism for which involves attenuation of the RAS/MAPK cell signaling pathway. […] Mutations in the Ras/mitogen activated protein kinase signaling pathways are known to be responsible for about 70% of NS cases. […] Several genes are involved in the genetic etiology of NS, with the key ones being PTPN11 accounting for 50% of genetically diagnosed cases, SOS1 responsible for 10-13% of cases, and RAF1 or RIT1 – each contributing to an additional 5% of cases. Correlations between phenotype and genotype exist, and identifying the genetic cause can shed light on expected symptoms. For example, mutations in the PTPN11 gene are associated with an increased tendency for pulmonary stenosis or leukemia, while mutations in the SOS1 gene are linked to relatively normal development and stature compared to other NS cases. About 15-20% of NS cases remain genetically undiagnosed.

• #43 NOONAN SYNDROME

  https://medicover-genetics.com/product/noonan-syndrome/

  Noonan syndrome is an autosomal dominant inherited disorder with a broad, variable spectrum of symptoms, including facial dysmorphia, short stature, chest deformities and heart defects. It belongs to a group of cardiovascular conditions known as RASopathies, and in 50% of cases is due to pathogenic variants in the PTPN11 gene. […] The PTPN11 gene, which codes for a cytoplasmic protein tyrosine phosphatase (SHP-2), is the gene mainly affected in Noonan syndrome. Pathogenic variants in the PTPN11 gene, which almost exclusively lead to amino acid exchanges, are the molecular cause in about 50% of all Noonan patients investigated so far. […] Pathogenic variants have currently been identified in several other genes, including the RASERK-MAP kinase signal transduction in Noonan syndrome. Mutations in the SOS1 (Son of Sevenless) gene were detected in up to 15% of Noonan patients who did not have a mutation in the PTPN11 gene. Pathogenic variants in the RAF1 gene could be identified in about 8% of Noonan patients. Almost all patients with RAF1 mutations show hypertrophic cardiomyopathy. Other genes include RIT1 (approximately 5% of patients) and KRAS (approximately 3% of patients), pathogenic variants here predominantly lead to severe phenotypes.

• #44 Novel insights in Noonan syndrome

  https://www.oatext.com/novel-insights-in-noonan-syndrome.php

  For instance, NS type 1 (MIM 163950), due to PTPN11 mutations, is characterized by frequent pulmonary stenosis and atrial septal abnormality, shorter stature, lower insulin growth factor-1 (IGF1) levels, more bleeding diathesis and juvenile myelomonocytic leukaemia. Whereas, in NS type 3 (MIM 609942), due to KRAS mutations, hypertrophic cardiomyopathy and naevi, lentigo, and caf au lait spots are typical.

• #45 Effects of Noonan Syndrome-Germline Mutations on Mitochondria and Energy Metabolism

  https://www.mdpi.com/2073-4409/11/19/3099

  Noonan syndrome (NS) and related Noonan syndrome with multiple lentigines (NSML) contribute to the pathogenesis of human diseases in the RASopathy family. […] These genes encode proteins that participate in, or regulate, RAS/MAPK signalling. The RAS pathway regulates cellular metabolism by controlling mitochondrial homeostasis, dynamics, and energy production; however, little is known about the role of mitochondrial metabolism in NS and NSML. […] This review describes the pathophysiological impact of NS and NSML-related germline mutations on cell metabolism. […] The RAS-MAPK pathway plays a profound role in developmental, endocrinal and metabolic processes, which comprises the cascade of downstream signals involving a coordinated action of proteins stimulated by extracellular factors.

• #46 Effects of Noonan Syndrome-Germline Mutations on Mitochondria and Energy Metabolism

  https://www.mdpi.com/2073-4409/11/19/3099

  Mitochondria are the major source of adenosine triphosphate (ATP), synthesized by the mitochondrial respiratory chain through the process of oxidative phosphorylation (OXPHOS). […] Though OXPHOS accounts for most of the energy produced in the cell, it is accompanied by physiological production of reactive oxygen species. […] Many diseases such as mitochondrial diseases, metabolic syndrome, neurodegenerative diseases and cancer arise when the mitochondria are perturbed by genetic or environmental toxin-mediated cues causing defects in the structural composition of the mitochondrial membrane, defects in ETC protein complexes, defects of mitochondrial protein import or defects in mitochondrial motility. […] The metabolic effects of hepatic SHP2 deletion in mice fed with a high-fat diet (HFD) have been studied to investigate further its role in lipid metabolism and energy balance.

• #47 Effects of Noonan Syndrome-Germline Mutations on Mitochondria and Energy Metabolism

  https://www.mdpi.com/2073-4409/11/19/3099

  PTPN11 accounts for the majority of germline mutations responsible for NS and NSML, followed by SOS1, KRAS isoform (except HRAS), RAF1 and SHOC2. […] These genes play an essential role in the pathogenesis of mitochondrial/metabolic-related disorders. […] The longer time an active RAS (KRAS) mutant is expressed on a cell, it leaves the cell with persistent dysfunctional mitochondria resulting in a metabolic adaptation. […] A profound influence of GOF PTPN11 (SHP2) mutation on mitochondrial cytochrome oxidase and cytochrome C led to a decrease in mitochondrial membrane permeability (MMP), increased ROS production, and decreased ATP production. […] These changes signal bioenergetic stress and may result in the release of apoptotic factors, culminating in cell death and accumulated ROS, which may cause oxidative damage in tissues, potentiating tissue failure.

• #48 Effects of Noonan Syndrome-Germline Mutations on Mitochondria and Energy Metabolism

  https://www.mdpi.com/2073-4409/11/19/3099

  PTPN11 accounts for the majority of germline mutations responsible for NS and NSML, followed by SOS1, KRAS isoform (except HRAS), RAF1 and SHOC2. […] These genes play an essential role in the pathogenesis of mitochondrial/metabolic-related disorders. […] The longer time an active RAS (KRAS) mutant is expressed on a cell, it leaves the cell with persistent dysfunctional mitochondria resulting in a metabolic adaptation. […] A profound influence of GOF PTPN11 (SHP2) mutation on mitochondrial cytochrome oxidase and cytochrome C led to a decrease in mitochondrial membrane permeability (MMP), increased ROS production, and decreased ATP production. […] These changes signal bioenergetic stress and may result in the release of apoptotic factors, culminating in cell death and accumulated ROS, which may cause oxidative damage in tissues, potentiating tissue failure.

• #49 Mechanism and treatment for learning and memory deficits in mouse models of Noonan syndrome | Nature Neuroscience

  https://www.nature.com/articles/nn.3863

  In Noonan syndrome (NS) 30-50% of subjects show cognitive deficits of unknown etiology and with no known treatment. Here, we report that knock-in mice expressing either of two NS-associated mutations in Ptpn11, which encodes the nonreceptor protein tyrosine phosphatase Shp2, show hippocampal-dependent impairments in spatial learning and deficits in hippocampal long-term potentiation (LTP). […] Our results demonstrate that increased basal Erk activity and corresponding baseline increases in excitatory synaptic function are responsible for the LTP impairments and, consequently, the learning deficits in mouse models of NS. These data also suggest that lovastatin or MEK inhibitors may be useful for treating the cognitive deficits in NS.

• #50 Mechanism and treatment for learning and memory deficits in mouse models of Noonan syndrome | Nature Neuroscience

  https://www.nature.com/articles/nn.3863

  In Noonan syndrome (NS) 30-50% of subjects show cognitive deficits of unknown etiology and with no known treatment. Here, we report that knock-in mice expressing either of two NS-associated mutations in Ptpn11, which encodes the nonreceptor protein tyrosine phosphatase Shp2, show hippocampal-dependent impairments in spatial learning and deficits in hippocampal long-term potentiation (LTP). […] Our results demonstrate that increased basal Erk activity and corresponding baseline increases in excitatory synaptic function are responsible for the LTP impairments and, consequently, the learning deficits in mouse models of NS. These data also suggest that lovastatin or MEK inhibitors may be useful for treating the cognitive deficits in NS.

• #51 Research on the Pathogenesis of Cognitive and Neurofunctional Impairments in Patients with Noonan Syndrome: The Role of Rat Sarcoma–Mitogen Activated Protein Kinase Signaling Pathway Gene Disturbances

  https://www.mdpi.com/2073-4425/14/12/2173

  The neurobiological mechanisms leading to cognitive deficits in some patients with Noonan syndrome are not yet well known. However, experimental animal models have suggested a possible association with molecular defects within the RAS/MAPK signal transduction pathway. […] It is highly plausible that cognitive deficits, as well as differences in brain structures, might be associated with mutations in particular genes leading to a dysregulation of the RAS/MAPK pathway. […] Accurate evaluation of neuropsychological profiles and underlying possible functional and structural abnormalities (including the assessment of microstructural white matter alterations as well as rsFC analysis) in Noonan syndrome patients gives us a better understanding of the essential impact of the RAS/MAPK signaling pathway’s dysregulation on human brain function.

• #52 Mechanism and treatment for learning and memory deficits in mouse models of Noonan syndrome | Nature Neuroscience

  https://www.nature.com/articles/nn.3863

  In Noonan syndrome (NS) 30-50% of subjects show cognitive deficits of unknown etiology and with no known treatment. Here, we report that knock-in mice expressing either of two NS-associated mutations in Ptpn11, which encodes the nonreceptor protein tyrosine phosphatase Shp2, show hippocampal-dependent impairments in spatial learning and deficits in hippocampal long-term potentiation (LTP). […] Our results demonstrate that increased basal Erk activity and corresponding baseline increases in excitatory synaptic function are responsible for the LTP impairments and, consequently, the learning deficits in mouse models of NS. These data also suggest that lovastatin or MEK inhibitors may be useful for treating the cognitive deficits in NS.

• #53 Research on the Pathogenesis of Cognitive and Neurofunctional Impairments in Patients with Noonan Syndrome: The Role of Rat Sarcoma–Mitogen Activated Protein Kinase Signaling Pathway Gene Disturbances

  https://www.mdpi.com/2073-4425/14/12/2173

  The neurobiological mechanisms leading to cognitive deficits in some patients with Noonan syndrome are not yet well known. However, experimental animal models have suggested a possible association with molecular defects within the RAS/MAPK signal transduction pathway. […] It is highly plausible that cognitive deficits, as well as differences in brain structures, might be associated with mutations in particular genes leading to a dysregulation of the RAS/MAPK pathway. […] Accurate evaluation of neuropsychological profiles and underlying possible functional and structural abnormalities (including the assessment of microstructural white matter alterations as well as rsFC analysis) in Noonan syndrome patients gives us a better understanding of the essential impact of the RAS/MAPK signaling pathway’s dysregulation on human brain function.

• #54 Noonan syndrome: genetic and clinical update and treatment options | Anales de Pediatría

  https://www.analesdepediatria.org/en-noonan-syndrome-genetic-clinical-update-articulo-S2341287920300909

  Noonan syndrome (NS) is a relatively common genetic condition characterised by short stature, congenital heart defects, and distinctive facial features. […] NS and other clinically overlapping conditions such as NS with multiple lentigines (formerly called LEOPARD syndrome), cardiofaciocutaneous syndrome, or Costello syndrome, are caused by mutations in genes encoding proteins of the RAS-MAPKinases pathway. […] The role of RAS/MAPK hyper-activation in the pathophysiology of this group of disorders offers a unique opportunity for the development of targeted approaches. […] The RAS-MAPK cascade is a well-known intracellular signalling pathway triggered by the binding of extracellular ligands such as hormones, cytokines and growth factors end resulting in transcription in the cell nucleus, and is involved in cell proliferation, differentiation and apoptosis processes.

• #55 Noonan Syndrome: Clinical Aspects and Molecular Pathogenesis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2858523/

  The RAS-MAPK cascade is activated in response to cytokine, hormone and growth factor stimulation, and is a major mediator of early and late developmental processes, including morphology determination, organogenesis, synaptic plasticity processes and growth. […] Thus far, 7 genes (PTPN11, SOS1, KRAS, RAF1, BRAF, SHOC2 and MEK1, alias MAP2K1) have been causally related to NS or closely related conditions, including LEOPARD syndrome and Noonan-like syndrome with loose anagen hair. […] PTPN11 was discovered as a major NS disease gene by using a positional candidacy approach in 2001. […] Based on those efforts, it has now been established that PTPN11 mutations account for approximately 50% of NS, and are more prevalent among subjects with pulmonary valve stenosis and short stature, and less common in individuals with HCM and/or severe cognitive deficits.

• #56 Noonan syndrome: genetic and clinical update and treatment options | Anales de Pediatría

  https://www.analesdepediatria.org/en-noonan-syndrome-genetic-clinical-update-articulo-S2341287920300909

  Most of the mutations described in these genes lead to a gain of function, and at present it is believed that RASopathies result from such gain of function or at least dysregulation of the RAS-MAPK pathway. […] To date, mutations in more than 20 genes have been described in association with NS, the RASopathy with the greatest known locus heterogeneity. […] The RASopathy Expert Panel of the Clinical Genome Resource (ClinGen), funded by the National Institutes of Health of the United States, has recently published a guideline for the interpretation of 19 genes involved in RASopathies that also provides a classification of the strength of the clinical and experimental evidence available on the different variants and the correlated phenotypes. […] There are multiple descriptions of genotype-phenotype correlations in NS in the literature, although there are no exclusive phenotypic features of any given genotype, probably due to genetic and epigenetic factors that influence penetrance and expressivity.

• #57 Noonan syndrome

  https://atlasgeneticsoncology.org/cancer-prone-disease/10085/noonan-syndrome

  Noonan syndrome is an autosomal dominant disorder. […] A significant percentage of Noonan syndrome cases arise from de novo PTPN11 mutations. […] Increasing evidence supports that a number of Noonan syndrome-causative mutations promote SHP-2 gain-of-function by destabilizing the catalytically inactive conformation of the protein, and prolong signal flux through the RAS/MAPK pathway in a ligand-dependent manner. […] Somatic activating mutations in PTPN11 have been documented in a heterogeneous group of hematologic malignancies and pre-leukemic disorders, and rarely in certain solid tumors.

• #58 Noonan Syndrome: Clinical Aspects and Molecular Pathogenesis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2858523/

  Noonan syndrome (NS) is caused by mutations in the PTPN11, SOS1, KRAS, RAF1, BRAF and MEK1 (MAP2K1) genes, accounting for approximately 70% of affected individuals. […] SHP2 (encoded by PTPN11), SOS1, BRAF, RAF1 and MEK1 positively contribute to RAS-MAPK signaling, and possess complex autoinhibitory mechanisms that are impaired by mutations. […] Similarly, reduced GTPase activity or increased guanine nucleotide release underlie the aberrant signal flow through the MAPK cascade promoted by most KRAS mutations. […] These recent discoveries demonstrate that the substantial phenotypic variation characterizing NS and related conditions can be ascribed, in part, to the gene mutated and even the specific molecular lesion involved. […] NS is genetically heterogeneous, and, based upon the recent discoveries of the underlying disease genes, it can now be regarded as a disorder of upregulated RAS-MAPK signaling.

• #59 Noonan Syndrome: Clinical Aspects and Molecular Pathogenesis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2858523/

  Noonan syndrome (NS) is caused by mutations in the PTPN11, SOS1, KRAS, RAF1, BRAF and MEK1 (MAP2K1) genes, accounting for approximately 70% of affected individuals. […] SHP2 (encoded by PTPN11), SOS1, BRAF, RAF1 and MEK1 positively contribute to RAS-MAPK signaling, and possess complex autoinhibitory mechanisms that are impaired by mutations. […] Similarly, reduced GTPase activity or increased guanine nucleotide release underlie the aberrant signal flow through the MAPK cascade promoted by most KRAS mutations. […] These recent discoveries demonstrate that the substantial phenotypic variation characterizing NS and related conditions can be ascribed, in part, to the gene mutated and even the specific molecular lesion involved. […] NS is genetically heterogeneous, and, based upon the recent discoveries of the underlying disease genes, it can now be regarded as a disorder of upregulated RAS-MAPK signaling.

• #60 Mutation-Specific Mechanisms of Hyperactivation of Noonan Syndrome SOS Molecules Detected with Single-molecule Imaging in Living Cells | Scientific Reports

  https://www.nature.com/articles/s41598-017-14190-6

  Noonan syndrome (NS) is a congenital hereditary disorder associated with developmental and cardiac defects. Some patients with NS carry mutations in SOS, a guanine nucleotide exchange factor (GEF) for the small GTPase RAS. NS mutations have been identified not only in the GEF domain, but also in various domains of SOS, suggesting that multiple mechanisms disrupt SOS function. […] The association and dissociation kinetics between SOS tagged with a fluorescent protein and the living cell surface were observed in single molecules. All three mutants showed increased affinity for the plasma membrane, inducing excessive RAS signalling. However, the mechanisms by which their affinity was increased were specific to each mutant. Conformational disorder in the resting state, increased probability of a conformational change on the plasma membrane, and an increased association rate constant with the membrane receptor are the suggested mechanisms.

• #61 Mutation-Specific Mechanisms of Hyperactivation of Noonan Syndrome SOS Molecules Detected with Single-molecule Imaging in Living Cells | Scientific Reports

  https://www.nature.com/articles/s41598-017-14190-6

  The mechanisms that induce excessive affinity for the cell surface are specific for each NS mutant. Membrane affinity is determined by the balance between association and dissociation. […] The differential properties of the three NS mutants in inducing the hyperassociation of SOS with the cell surface may cause mutant-specific dynamics of RAS activation, which cannot be explained simply by the cell-surface density of the SOS molecules.

• #62 Noonan Syndrome: Clinical Aspects and Molecular Pathogenesis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2858523/

  Overall, the available genetic, modeling, biochemical and functional data support a model in which distinct gain-of-function thresholds for SHP2 activity are required to induce cell-, tissue- or developmental-specific phenotypes, each depending on the transduction network context involved in the phenotype.

• #63 Noonan Syndrome: Clinical Aspects and Molecular Pathogenesis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2858523/

  Most of the mutations affect residues involved in the N-SH2/PTP interdomain binding network that stabilizes SHP2 in its catalytically inactive conformation or are in close spatial proximity to them. […] A distinct class of PTPN11 mutations has been identified to underlie LEOPARD syndrome (LS; OMIM 151100). […] PTPN11 mutation screening on a relatively large number of children with NS and JMML has demonstrated the presence of germline mutations in the majority of cases, with one mutation rarely observed in NS, c.218CT (Thr73Ile), occurring in a large percentage of children. […] The association between this specific amino acid change and JMML in NS and the key-role of SHP2 in RAS signaling and hematopoiesis suggested that a distinct class of lesions in the gene, possibly acquired as a somatic event, might play a role in leukemogenesis.

• #64 Noonan Syndrome With Multiple Lentigines | Actas Dermo-Sifiliográficas

  https://www.actasdermo.org/en-translated-article-noonan-syndrome-with-articulo-S0001731024000760

  Noonan syndrome with multiple lentigines (NSML, OMIM 151100) is a rare genodermatosis of autosomal dominant inheritance, high penetrance, and variable expressivity, previously known as the LEOPARD is an acronym for the major features of this disorder, including multiple Lentigines, ECG conduction abnormalities, Ocular hypertelorism, Pulmonic stenosis, Abnormal genitalia, Retardation of growth, and sensorineural Deafness. […] In 85% of the cases, NSML is associated with mutations in the PTPN11 gene, which encodes the tyrosine phosphatase SHP2 protein involved in the RAS-MAPK signaling pathway involved in cell proliferation and differentiation processes. The pathogenesis of lentigenes development is explained by an increased melanin synthesis of melanocytes due to the SHP2 mutation, along with the activation of Akt/mTOR and STAT3 signaling pathways. […] The disruption of these signaling pathways involved in tumorigenesis can increase the risk of various neoplasms in NSML, including melanoma, with 5 cases being reported to this date.

• #65 Noonan Syndrome: Clinical Aspects and Molecular Pathogenesis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2858523/

  Most of the mutations affect residues involved in the N-SH2/PTP interdomain binding network that stabilizes SHP2 in its catalytically inactive conformation or are in close spatial proximity to them. […] A distinct class of PTPN11 mutations has been identified to underlie LEOPARD syndrome (LS; OMIM 151100). […] PTPN11 mutation screening on a relatively large number of children with NS and JMML has demonstrated the presence of germline mutations in the majority of cases, with one mutation rarely observed in NS, c.218CT (Thr73Ile), occurring in a large percentage of children. […] The association between this specific amino acid change and JMML in NS and the key-role of SHP2 in RAS signaling and hematopoiesis suggested that a distinct class of lesions in the gene, possibly acquired as a somatic event, might play a role in leukemogenesis.

• #66 Noonan Syndrome: Clinical Aspects and Molecular Pathogenesis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2858523/

  Most of the mutations affect residues involved in the N-SH2/PTP interdomain binding network that stabilizes SHP2 in its catalytically inactive conformation or are in close spatial proximity to them. […] A distinct class of PTPN11 mutations has been identified to underlie LEOPARD syndrome (LS; OMIM 151100). […] PTPN11 mutation screening on a relatively large number of children with NS and JMML has demonstrated the presence of germline mutations in the majority of cases, with one mutation rarely observed in NS, c.218CT (Thr73Ile), occurring in a large percentage of children. […] The association between this specific amino acid change and JMML in NS and the key-role of SHP2 in RAS signaling and hematopoiesis suggested that a distinct class of lesions in the gene, possibly acquired as a somatic event, might play a role in leukemogenesis.

• #67

  https://www.omim.org/entry/163950

  In more than 50% of patients with Noonan syndrome, Tartaglia et al. (2001) identified mutations in the PTPN11 gene (see, e.g., 176876.0001-176876.0003). All the PTPN11 missense mutations were clustered in the interacting portions of the amino N-SH2 (Src homology 2) domain and the phosphotyrosine phosphatase (PTP) domains, which are involved in switching the protein between its inactive and active conformations. An energetics-based structural analysis of 2 N-SH2 mutants indicated that in these cases there may be a significant shift of the equilibrium favoring the active conformation. The findings suggested that gain-of-function changes resulting in excessive SHP2 activity underlie the pathogenesis of Noonan syndrome. […] After germline mutations in PTPN11 (176876) were demonstrated in the Noonan syndrome, Tartaglia et al. (2003) investigated defects in PTPN11 in myeloid disorders including cases of juvenile myelomonocytic leukemia (JMML; 607785) in children with Noonan syndrome. Specific mutations in PTPN11 associated with isolated JMML occurred as somatic changes and had never been observed as germline defects, leading Tartaglia et al. (2003) to speculate that these molecular defects are stronger and associated with embryonic lethality. Conversely, most mutations in PTPN11 associated with Noonan syndrome, which were sufficient to perturb developmental processes, were not fully leukemogenic, suggesting a milder gain-of-function effect.

• #68 Noonan syndrome pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Noonan_syndrome_pathophysiology

  Them most studied mutation leading to Noonan syndrome involves the N-SH2 domain of the SHP-2 protein involved in signal transduction as part of the RAS-MAP Kinase pathway. This mutation allows SHP-2 to become constitutively activated leading to an increase in downstream signaling and disruption of embryogenesis. […] The functional pathogenesis of Noonan syndrome has been mostly elaborated in the context of PTPN11 mutations. The PTPN11 gene codes for the SHP-2 protein, a cytoplasmic SH2 domain-containing protein tyrosine phosphatase that is ubiquitous in adult and embryonic tissues. Functionally, the SHP-2 protein acts as an intracellular signal transducer that has a particularily important role during development. It is mainly involved in mesodermal patterning and gastrulation during early embryogenesis but also plays a role in the formation of terminal and skeletal structures, semilunar valvulogenesis, and hematopoiesis. It has been shown that SHP-2 positively controls the activation of the RAS/MAPK cascade, the SRC family kinase, and IL-1/TNF-dependent NF-B activation.

• #69 Noonan syndrome pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Noonan_syndrome_pathophysiology

  Them most studied mutation leading to Noonan syndrome involves the N-SH2 domain of the SHP-2 protein involved in signal transduction as part of the RAS-MAP Kinase pathway. This mutation allows SHP-2 to become constitutively activated leading to an increase in downstream signaling and disruption of embryogenesis. […] The functional pathogenesis of Noonan syndrome has been mostly elaborated in the context of PTPN11 mutations. The PTPN11 gene codes for the SHP-2 protein, a cytoplasmic SH2 domain-containing protein tyrosine phosphatase that is ubiquitous in adult and embryonic tissues. Functionally, the SHP-2 protein acts as an intracellular signal transducer that has a particularily important role during development. It is mainly involved in mesodermal patterning and gastrulation during early embryogenesis but also plays a role in the formation of terminal and skeletal structures, semilunar valvulogenesis, and hematopoiesis. It has been shown that SHP-2 positively controls the activation of the RAS/MAPK cascade, the SRC family kinase, and IL-1/TNF-dependent NF-B activation.

• #70 Noonan Syndrome | Children’s Hospital of Philadelphia

  https://www.chop.edu/conditions-diseases/noonan-syndrome

  Noonan syndrome is caused by alterations (also known as mutations) at specific areas within a person’s genetic information. […] Noonan syndrome is caused by mutations in one of several different genes, including PTPN11, SOS1, KRAS, NRAS, RAF1, BRAF or MEK1. Together mutations in these genes account for 70-75 percent of Noonan syndrome cases. […] Noonan syndrome is an autosomal dominant condition, which means that alterations involving only one of the two copies of a Noonan syndrome-associated gene are sufficient to cause the disorder. […] The PTPN11, SOS1, KRAS, NRAS, RAF1, BRAF, or MEK1 genes produce proteins that regulate key signaling pathways within cells required for the proper formation of tissues during development. Noonan syndrome-associated mutations cause the resulting proteins to be continuously active, instead of switching on and off in response to specific external cues. This disrupts the normal pattern of signals that control cell growth and division, and leads to the characteristic features of Noonan syndrome and the increased risk for developing benign or malignant tumors. […] There are likely to be additional, undiscovered genes that play a role in the development of Noonan syndrome for the remaining 25-30 percent of patients.

• #71 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Noonan-Syndrome-History.aspx

  Noonan syndrome is a pleiomorphic autosomal dominant disorder with cardinal features such as short stature, distinctive facial dysmorphia, webbed neck, and heart defects. […] significant progress has been made in elucidating the pathogenesis and genetics of this disorder. […] In 1994, the gene for Noonan syndrome was mapped to the long arm of chromosome 12 and named NS1. […] In 2001, Tartaglia and his co-workers found a mutation in the protein tyrosine phosphatase nonreceptor type 11 gene (PTPN11), which was the first molecular cause of Noonan syndrome. […] Subsequent studies of PTPN11 deficiency in a mouse model revealed that its protein product, tyrosine phosphatase SHP-2, was pivotal for the embryologic development of the semilunar cardiac valves. […] It has been also confirmed that mutations in the PTPN11 gene have a very high incidence of congenital heart disease of at least 80%.

• #72 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Noonan-Syndrome-History.aspx

  Noonan syndrome is a pleiomorphic autosomal dominant disorder with cardinal features such as short stature, distinctive facial dysmorphia, webbed neck, and heart defects. […] significant progress has been made in elucidating the pathogenesis and genetics of this disorder. […] In 1994, the gene for Noonan syndrome was mapped to the long arm of chromosome 12 and named NS1. […] In 2001, Tartaglia and his co-workers found a mutation in the protein tyrosine phosphatase nonreceptor type 11 gene (PTPN11), which was the first molecular cause of Noonan syndrome. […] Subsequent studies of PTPN11 deficiency in a mouse model revealed that its protein product, tyrosine phosphatase SHP-2, was pivotal for the embryologic development of the semilunar cardiac valves. […] It has been also confirmed that mutations in the PTPN11 gene have a very high incidence of congenital heart disease of at least 80%.

• #73

  https://link.springer.com/article/10.1007/s00431-023-05263-y

  Noonan syndrome belongs to the family of RASopathies, a group of multiple congenital anomaly disorders caused by pathogenic variants in genes encoding components or regulators of the RAS/mitogen-activated protein kinase (MAPK) signalling pathway. […] Collectively, all these pathogenic variants lead to increased RAS/MAPK activation. […] The better understanding of the molecular mechanisms underlying the different manifestations of NS and RASopathies has led to the identification of molecular targets for specific pharmacological interventions. […] Given the key role of RAS/MAPK dysregulation in the pathophysiology of NS and other RASopathies, therapeutic strategies aimed at reducing this activation appear very promising. […] Many specific agents (e.g. SHP2 and MEK inhibitors) have been developed and are now in clinical use for the treatment of RAS/MAPK-driven malignancies and may represent options for the treatment of patients with RASopathies.

• #74

  https://link.springer.com/article/10.1007/s00431-023-05263-y

  Drug repositioning of these molecules represents a challenging approach to treat or prevent medical complications associated with RASopathies. […] The identification of pathophysiological mechanisms provides new insights into the development of specific therapeutic strategies, in particular treatment aimed at reducing RAS/MAPK hyperactivation. […] The discovery of the genetic bases of NS and other RASopathies over the last 20 years and the subsequent development of animal models has led to a better understanding of the molecular mechanisms underlying the different manifestations and helped to identify molecular targets for specific pharmacological interventions. […] A better understanding of the pathophysiology of NS and other RASopathies has also highlighted specific defects at the subcellular, cellular, or tissue levels that may represent potent targets for selective therapies.

• #75

  https://link.springer.com/article/10.1007/s00431-023-05263-y

  Noonan syndrome belongs to the family of RASopathies, a group of multiple congenital anomaly disorders caused by pathogenic variants in genes encoding components or regulators of the RAS/mitogen-activated protein kinase (MAPK) signalling pathway. […] Collectively, all these pathogenic variants lead to increased RAS/MAPK activation. […] The better understanding of the molecular mechanisms underlying the different manifestations of NS and RASopathies has led to the identification of molecular targets for specific pharmacological interventions. […] Given the key role of RAS/MAPK dysregulation in the pathophysiology of NS and other RASopathies, therapeutic strategies aimed at reducing this activation appear very promising. […] Many specific agents (e.g. SHP2 and MEK inhibitors) have been developed and are now in clinical use for the treatment of RAS/MAPK-driven malignancies and may represent options for the treatment of patients with RASopathies.

• #76

  https://link.springer.com/article/10.1007/s00431-023-05263-y

  Noonan syndrome belongs to the family of RASopathies, a group of multiple congenital anomaly disorders caused by pathogenic variants in genes encoding components or regulators of the RAS/mitogen-activated protein kinase (MAPK) signalling pathway. […] Collectively, all these pathogenic variants lead to increased RAS/MAPK activation. […] The better understanding of the molecular mechanisms underlying the different manifestations of NS and RASopathies has led to the identification of molecular targets for specific pharmacological interventions. […] Given the key role of RAS/MAPK dysregulation in the pathophysiology of NS and other RASopathies, therapeutic strategies aimed at reducing this activation appear very promising. […] Many specific agents (e.g. SHP2 and MEK inhibitors) have been developed and are now in clinical use for the treatment of RAS/MAPK-driven malignancies and may represent options for the treatment of patients with RASopathies.

• #77

  https://link.springer.com/article/10.1007/s00431-023-05263-y

  Drug repositioning of these molecules represents a challenging approach to treat or prevent medical complications associated with RASopathies. […] The identification of pathophysiological mechanisms provides new insights into the development of specific therapeutic strategies, in particular treatment aimed at reducing RAS/MAPK hyperactivation. […] The discovery of the genetic bases of NS and other RASopathies over the last 20 years and the subsequent development of animal models has led to a better understanding of the molecular mechanisms underlying the different manifestations and helped to identify molecular targets for specific pharmacological interventions. […] A better understanding of the pathophysiology of NS and other RASopathies has also highlighted specific defects at the subcellular, cellular, or tissue levels that may represent potent targets for selective therapies.

• #78

  https://link.springer.com/article/10.1007/s00431-023-05263-y

  Drug repositioning of these molecules represents a challenging approach to treat or prevent medical complications associated with RASopathies. […] The identification of pathophysiological mechanisms provides new insights into the development of specific therapeutic strategies, in particular treatment aimed at reducing RAS/MAPK hyperactivation. […] The discovery of the genetic bases of NS and other RASopathies over the last 20 years and the subsequent development of animal models has led to a better understanding of the molecular mechanisms underlying the different manifestations and helped to identify molecular targets for specific pharmacological interventions. […] A better understanding of the pathophysiology of NS and other RASopathies has also highlighted specific defects at the subcellular, cellular, or tissue levels that may represent potent targets for selective therapies.

• #79 Mechanism and treatment for learning and memory deficits in mouse models of Noonan syndrome | Nature Neuroscience

  https://www.nature.com/articles/nn.3863

  In Noonan syndrome (NS) 30-50% of subjects show cognitive deficits of unknown etiology and with no known treatment. Here, we report that knock-in mice expressing either of two NS-associated mutations in Ptpn11, which encodes the nonreceptor protein tyrosine phosphatase Shp2, show hippocampal-dependent impairments in spatial learning and deficits in hippocampal long-term potentiation (LTP). […] Our results demonstrate that increased basal Erk activity and corresponding baseline increases in excitatory synaptic function are responsible for the LTP impairments and, consequently, the learning deficits in mouse models of NS. These data also suggest that lovastatin or MEK inhibitors may be useful for treating the cognitive deficits in NS.

• #80 Noonan syndrome: genetic and clinical update and treatment options | Anales de Pediatría

  https://www.analesdepediatria.org/en-noonan-syndrome-genetic-clinical-update-articulo-S2341287920300909

  Strategies aimed at decreasing activity in the RAS-MAPK pathway have attracted considerable attention, with of preclinical trials showing favourable results. […] Inhibition of the PI3/AKT/mTOR cascade with rapamycin has been proven to improve cardiac involvement in animal models of NS-ML, and the drug was effective in a critically ill patient. […] In short, the following are reasonable recommendations based on the current medical literature: Independently of the conditions established for the indication for treatment once it is approved, the decision to use rhGH in patients with NS should be made on a case-by-case basis.

• #81 Children with severe heart disease benefit from cancer medication – Innovative treatment reduces heart failure in children with Noonan syndrome – Radboudumc

  https://www.radboudumc.nl/en/news-items/2025/children-with-severe-heart-disease-benefit-from-cancer-medication

  Children with Noonan syndrome benefit from an innovative treatment when they suffer from severe RASopathy-associated hypertrophic cardiomyopathy, a disease which may lead to heart failure and death. […] Trametinib blocks this pathway, stopping cell growth. […] This same mechanism also plays a role in Noonan syndrome, where the abnormality in the RAS-MAPK signaling pathway causes hypertrophic cardiomyopathy. […] This targeted, innovative therapy can indeed help severely ill children, as shown by a retrospective study of 61 children. […] The study revealed that children who received trametinib had a lower risk of death, heart transplantation, or other major heart surgeries. […] Moreover, their cardiac status improved. […] Treating children with a particular drug without scientific evidence of its effectiveness cannot be done lightly. […] There are still a number of research questions to address: 'We want to know what the optimal dose is for a child, and how long we should administer the drug. […] But the fact that these results are promising is for sure.’

• #82

  https://insight.jci.org/articles/view/90220

  Noonan syndrome (NS) is a common autosomal dominant disorder that presents with short stature, craniofacial dysmorphism, and cardiac abnormalities. Activating mutations in the PTPN11 gene encoding for the Src homology 2 (SH2) domain-containing protein tyrosine phosphatase-2 (SHP2) causes approximately 50% of NS cases. […] Protein zero-related (PZR) is a SHP2-binding protein that is hyper-tyrosyl phosphorylated in the hearts of mice from NS and NSML, suggesting that PZR and the tyrosine kinase that catalyzes its phosphorylation represent common targets for these diseases. […] These results suggest that PZR/SHP2 signaling is a common target of both NS and NSML and that low-dose dasatinib may represent a unifying therapy for the treatment of PTPN11-related cardiomyopathies. […] Identifying core signaling components utilized by both NS- and NSML-related disorders could offer new insight into the progression of these diseases and potentially suggest novel therapeutic strategies to treat the more severe manifestations of NS.

• #83

  https://insight.jci.org/articles/view/90220

  In cultured fibroblasts derived from NS mice, dasatinib effectively inhibited PZR tyrosyl phosphorylation and SHP2 binding. […] Our data further show that parameters of cardiomyopathy and fibrosis in both NS and NSML are reversed by low-dose dasatinib treatment. […] These findings demonstrate that postdevelopmental treatment with dasatinib in a NS mouse model alleviates the contractile dysfunction of the myocardium. […] Collectively, these results support the conclusion that low-dose dasatinib acts to effectively rescue both NS- and NSML-mediated effects in the myocardium.

• #84

  https://insight.jci.org/articles/view/90220

  In cultured fibroblasts derived from NS mice, dasatinib effectively inhibited PZR tyrosyl phosphorylation and SHP2 binding. […] Our data further show that parameters of cardiomyopathy and fibrosis in both NS and NSML are reversed by low-dose dasatinib treatment. […] These findings demonstrate that postdevelopmental treatment with dasatinib in a NS mouse model alleviates the contractile dysfunction of the myocardium. […] Collectively, these results support the conclusion that low-dose dasatinib acts to effectively rescue both NS- and NSML-mediated effects in the myocardium.

• #85

  https://insight.jci.org/articles/view/90220

  In cultured fibroblasts derived from NS mice, dasatinib effectively inhibited PZR tyrosyl phosphorylation and SHP2 binding. […] Our data further show that parameters of cardiomyopathy and fibrosis in both NS and NSML are reversed by low-dose dasatinib treatment. […] These findings demonstrate that postdevelopmental treatment with dasatinib in a NS mouse model alleviates the contractile dysfunction of the myocardium. […] Collectively, these results support the conclusion that low-dose dasatinib acts to effectively rescue both NS- and NSML-mediated effects in the myocardium.

• #86

  https://insight.jci.org/articles/view/90220

  In cultured fibroblasts derived from NS mice, dasatinib effectively inhibited PZR tyrosyl phosphorylation and SHP2 binding. […] Our data further show that parameters of cardiomyopathy and fibrosis in both NS and NSML are reversed by low-dose dasatinib treatment. […] These findings demonstrate that postdevelopmental treatment with dasatinib in a NS mouse model alleviates the contractile dysfunction of the myocardium. […] Collectively, these results support the conclusion that low-dose dasatinib acts to effectively rescue both NS- and NSML-mediated effects in the myocardium.

• #87

  https://link.springer.com/article/10.1007/s00431-023-05263-y

  Drug repositioning of these molecules represents a challenging approach to treat or prevent medical complications associated with RASopathies. […] The identification of pathophysiological mechanisms provides new insights into the development of specific therapeutic strategies, in particular treatment aimed at reducing RAS/MAPK hyperactivation. […] The discovery of the genetic bases of NS and other RASopathies over the last 20 years and the subsequent development of animal models has led to a better understanding of the molecular mechanisms underlying the different manifestations and helped to identify molecular targets for specific pharmacological interventions. […] A better understanding of the pathophysiology of NS and other RASopathies has also highlighted specific defects at the subcellular, cellular, or tissue levels that may represent potent targets for selective therapies.

• #88 European network on Noonan syndrome and related disorders — ERA-LEARN

  https://www.era-learn.eu/network-information/networks/sc1-bhc-04-2018/1st-ejp-rd-joint-transnational-call-for-rare-diseases-research-project-jtc-2019/european-network-on-noonan-syndrome-and-related-disorders

  RASopathies share upregulation of RAS signaling via the MAPK and/or PI3K-AKT-mTOR pathways as pathogenetic mechanism. […] There are, however, fundamental questions about the mechanisms of disease that are still unanswered, and a significant number of patients remains molecularly unexplained. […] Goals of the proposed research, which is the natural follow-up of a previously funded E-Rare project, are to further explore the molecular bases of these disorders. Research will be directed to resolve the functional consequences of a large panel of uncharacterized RASopathy-causing mutations, generate in vitro and in vivo gene/mutation-specific models, characterize novel circuits modulating RAS signaling, explore the pathophysiology of key complications of these diseases, and further identify novel disease genes.

• #89 European network on Noonan syndrome and related disorders — ERA-LEARN

  https://www.era-learn.eu/network-information/networks/sc1-bhc-04-2018/1st-ejp-rd-joint-transnational-call-for-rare-diseases-research-project-jtc-2019/european-network-on-noonan-syndrome-and-related-disorders

  RASopathies share upregulation of RAS signaling via the MAPK and/or PI3K-AKT-mTOR pathways as pathogenetic mechanism. […] There are, however, fundamental questions about the mechanisms of disease that are still unanswered, and a significant number of patients remains molecularly unexplained. […] Goals of the proposed research, which is the natural follow-up of a previously funded E-Rare project, are to further explore the molecular bases of these disorders. Research will be directed to resolve the functional consequences of a large panel of uncharacterized RASopathy-causing mutations, generate in vitro and in vivo gene/mutation-specific models, characterize novel circuits modulating RAS signaling, explore the pathophysiology of key complications of these diseases, and further identify novel disease genes.

• #90 Mutation-Specific Mechanisms of Hyperactivation of Noonan Syndrome SOS Molecules Detected with Single-molecule Imaging in Living Cells | Scientific Reports

  https://www.nature.com/articles/s41598-017-14190-6

  Clarification of the pathological mechanism of each NS mutant in hyperactivating the RASMAPK pathway is crucial to establishing techniques for the rational treatment of NS. […] Mutations in the Cdc25 domain may directly increase the GEF activity of SOS, inducing the hyperactivation of the RASMAPK pathway. However, mutations in the other domains must affect RASMAPK activation through indirect mechanisms. […] The discovery of various genetic mutations in NS patients suggests that the common feature of NS (i.e., the excessive activation of the RASMAPK pathway) results from many molecular mechanisms. More than 30 different NS-related point mutations have been reported in the SOS molecule alone. […] A higher density of SOS on the cell surface simply increases the probability of it contacting the inactive form RAS, which is then activated by SOS.

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