Activation of multiple signaling pathways causes developmental defects in mice with a Noonan syndrome–associated Sos1 mutation

Chen, Peng Chieh; Wakimoto, Hiroko; Conner, David A.; Araki, Toshiyuki; Tao, Yuan Xiang; Roberts, Amy; Seidman, Christine E.; Bronson, Roderick T.; Neel, Benjamin G.; Seidman, Jonathan G.; Kucherlapati, Raju

doi:10.1172/jci43910

Cited by 100 publications

(91 citation statements)

References 67 publications

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“…In agreement with this, earlier reports incidentally showed that Mek inhibitors can rescue growth defect in other NS mouse models (RAF1 L613V/+ and SOS1 E846K/E846K ) [7,66]. Altogether, these reports suggest that pharmacological regulation of Ras/MAPK could be an alternative approach to treat short stature in NS patients, even though a lot requires to be accomplished to assess the efficacy and safety of these Figure 1.…”

Section: Role Of Ptpn11/shp2 Mutant Causing Ns In Ras/mapk Upregulatisupporting

confidence: 67%

“…However, in the cell or in vivo, these mutations result almost systematically in a higher-than-normal activation of the Ras/ MAPK pathway. This hyperactivation is thought to be responsible for the disease phenotype, as shown by studies in mice which began to explore the mechanisms involved in the pathogenicity of genes causing NS or other Rasopathies [5][6][7].…”

Section: Introductionmentioning

confidence: 99%

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Growth hormone and noonan syndrome: update in dysfunctional signaling aspects and in therapy for short stature

Raynal¹

2014

Horm Stud

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Short stature is a frequent feature of Noonan syndrome (NS), a disease caused by mutations of genes encoding components of the Ras/mitogen-activated protein kinases (MAPK) signalling pathway. To date numerous patients have been treated with growth hormone (GH) in various countries. However this treatment is still controversial, as its efficacy is a matter of debate. The final height gain of GH therapy represents 5 to 10 cm, at best, which is disappointing considering the length and burden of the treatment. The reasons explaining this lack of efficiency are poorly understood and they seemed to involve a waning effect after the first year of GH treatment or acceleration of bone maturation in patients on GH. Moreover, GH therapy raises questions about its safety, especially in subjects with NS who are at risk for cardiac defects and malignancies. Cases of severe adverse effects were described, yet too sporadically to conclude that they were certainly caused by GH therapy. Novels insights in understanding the dysfunction of GH-dependent processes in NS were recently reported and this manuscript aims at reviewing the latest advances. Clinical data suggested that growth retardation could be caused by a partial postreceptor resistance to GH, an impaired sensitivity to GH which could also explain the modest efficiency of GH therapy in NS patients. Similar observations were also obtained in a NS mouse model harboring a mutation in the gene encoding the tyrosine phosphatase Shp2. In the mouse, the mechanism of GH resistance is thought to involve upregulation by mutated Shp2 of GH-induced Ras/MAPK, a signaling pathway which seemed to play a negative regulatory role in the production of GH mediators involved in bone growth. Despite these recent finding, the underlying mechanisms of growth retardation and GH therapy in NS remain to be further explored in order to improve treatment for short stature.

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Section: Role Of Ptpn11/shp2 Mutant Causing Ns In Ras/mapk Upregulatisupporting

confidence: 67%

Section: Introductionmentioning

confidence: 99%

Growth hormone and noonan syndrome: update in dysfunctional signaling aspects and in therapy for short stature

Raynal¹

2014

Horm Stud

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“…Identifying the causative allele in each NS patient is likely to be critical for choosing an effective therapy. For example, mice that carry a Sos1 mutation develop multiple NS features, and these defects can be prevented or their expression reduced by MEK inhibitor treatment during the early stages of life (47). Postnatal MEK inhibitor treatment also reverses some NS symptoms in Raf1 mutant mice (48), and rapamycin normalizes HCM in LS mouse models (5).…”

Section: Significancementioning

confidence: 99%

Next-generation sequencing identifies rare variants associated with Noonan syndrome

Chen

Yin

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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157

148

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Noonan syndrome (NS) is a relatively common genetic disorder, characterized by typical facies, short stature, developmental delay, and cardiac abnormalities. Known causative genes account for 70-80% of clinically diagnosed NS patients, but the genetic basis for the remaining 20-30% of cases is unknown. We performed nextgeneration sequencing on germ-line DNA from 27 NS patients lacking a mutation in the known NS genes. We identified gainof-function alleles in Ras-like without CAAX 1 (RIT1) and mitogenactivated protein kinase kinase 1 (MAP2K1) and previously unseen loss-of-function variants in RAS p21 protein activator 2 (RASA2) that are likely to cause NS in these patients. Expression of the mutant RASA2, MAP2K1, or RIT1 alleles in heterologous cells increased RAS-ERK pathway activation, supporting a causative role in NS pathogenesis. Two patients had more than one disease-associated variant. Moreover, the diagnosis of an individual initially thought to have NS was revised to neurofibromatosis type 1 based on an NF1 nonsense mutation detected in this patient. Another patient harbored a missense mutation in NF1 that resulted in decreased protein stability and impaired ability to suppress RAS-ERK activation; however, this patient continues to exhibit a NS-like phenotype. In addition, a nonsense mutation in RPS6KA3 was found in one patient initially diagnosed with NS whose diagnosis was later revised to Coffin-Lowry syndrome. Finally, we identified other potential candidates for new NS genes, as well as potential carrier alleles for unrelated syndromes. Taken together, our data suggest that nextgeneration sequencing can provide a useful adjunct to RASopathy diagnosis and emphasize that the standard clinical categories for RASopathies might not be adequate to describe all patients.human genetics | developmental diseases | whole exome sequencing | PTPN11 | RAS

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“…RTK activation engenders RAS signaling to be turned on through GRB2, which has been implicated in the development of hypertrophy (46). In turn, GRB2 mediates the activation of SOS1, which is mutated in NS patients and mouse models leading to HCM (47). Also, SHP2 is a key component of multiple RTK, cytokine receptor and integrin signaling cascades.…”

Section: Pathophysiological Signaling: Experimental Relevance Of the mentioning

confidence: 99%

Signaling to Cardiac Hypertrophy: Insights from Human and Mouse RASopathies

Sala

Gallo

Leo

et al. 2012

Mol Med

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Activation of multiple signaling pathways causes developmental defects in mice with a Noonan syndrome–associated Sos1 mutation

Cited by 100 publications

References 67 publications

Growth hormone and noonan syndrome: update in dysfunctional signaling aspects and in therapy for short stature

Growth hormone and noonan syndrome: update in dysfunctional signaling aspects and in therapy for short stature

Next-generation sequencing identifies rare variants associated with Noonan syndrome

Signaling to Cardiac Hypertrophy: Insights from Human and Mouse RASopathies

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