scholarly journals The RASopathy Family: Consequences of Germline Activation of the RAS/MAPK Pathway

2018 ◽  
Vol 39 (5) ◽  
pp. 676-700 ◽  
Author(s):  
Mylène Tajan ◽  
Romain Paccoud ◽  
Sophie Branka ◽  
Thomas Edouard ◽  
Armelle Yart
Keyword(s):  
Noonan Syndrome ◽  
Mapk Pathway ◽  
Genetic Disorders ◽  
Mapk Signaling ◽  
Mendelian Inheritance ◽  
Disease Genes ◽  
Type I ◽  
Future Directions ◽  
Legius Syndrome ◽  
Anagen Hair

Abstract Noonan syndrome [NS; Mendelian Inheritance in Men (MIM) #163950] and related syndromes [Noonan syndrome with multiple lentigines (formerly called LEOPARD syndrome; MIM #151100), Noonan-like syndrome with loose anagen hair (MIM #607721), Costello syndrome (MIM #218040), cardio-facio-cutaneous syndrome (MIM #115150), type I neurofibromatosis (MIM #162200), and Legius syndrome (MIM #611431)] are a group of related genetic disorders associated with distinctive facial features, cardiopathies, growth and skeletal abnormalities, developmental delay/mental retardation, and tumor predisposition. NS was clinically described more than 50 years ago, and disease genes have been identified throughout the last 3 decades, providing a molecular basis to better understand their physiopathology and identify targets for therapeutic strategies. Most of these genes encode proteins belonging to or regulating the so-called RAS/MAPK signaling pathway, so these syndromes have been gathered under the name RASopathies. In this review, we provide a clinical overview of RASopathies and an update on their genetics. We then focus on the functional and pathophysiological effects of RASopathy-causing mutations and discuss therapeutic perspectives and future directions.

scholarly journals Detection of brain somatic variation in epilepsy-associated developmental lesions

2021 ◽  
Author(s):  
Tracy A Bedrosian ◽  
Katherine E Miller ◽  
Olivia E Grischow ◽  
Hyojung Yoon ◽  
Kathleen M Schieffer ◽  
...  
Keyword(s):  
Focal Epilepsy ◽  
Mapk Pathway ◽  
Focal Cortical Dysplasia ◽  
Somatic Mosaicism ◽  
Cortical Dysplasia ◽  
Disease Genes ◽  
Low Grade ◽  
Type I ◽  
Somatic Variation ◽  
Tissue Samples

Epilepsy-associated developmental lesions, including malformations of cortical development and low-grade developmental tumors, represent a major cause of drug-resistant seizures requiring surgical intervention in children. Brain-restricted somatic mosaicism has been implicated in the genetic etiology of these lesions; however, many contributory genes remain unidentified. We enrolled 50 children undergoing epilepsy surgery into a translational research study. We performed exome and RNA-sequencing of resected brain tissue samples to identify somatic variation. We uncovered candidate disease-causing somatic variation affecting 28 patients (56%), as well as candidate germline variants affecting 4 patients (8%). We confirmed somatic findings using high-depth targeted DNA sequencing. In agreement with previous studies, we identified somatic variation affecting SLC35A2 and MTOR pathway genes in patients with focal cortical dysplasia. Somatic gains of chromosome 1q were detected in 30% (3 of 10) Type I FCD patients. Somatic variation of MAPK pathway genes (i.e., FGFR1, FGFR2, BRAF, KRAS) was associated with low-grade epilepsy-associated developmental tumors. Somatic structural variation accounted for over one-half of epilepsy-associated tumor diagnoses. Sampling across multiple anatomic regions revealed that somatic variant allele fractions vary widely within epileptogenic tissue. Finally, we identified putative disease-causing variants in genes (EEF2, NAV2, PTPN11) not yet associated with focal cortical dysplasia. These results further elucidate the genetic basis of structural brain abnormalities leading to focal epilepsy in children and point to new candidate disease genes.

p21-Activated Kinase 1 Regulates Hyperproliferation of Nf1 Haploinsufficient Mast Cells In Vitro and In Vivo Via Activation of the MAPK Pathway.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3063-3063
Author(s):  
Andrew S. McDaniel
Keyword(s):  
Mast Cells ◽  
Mammalian Cells ◽  
Rho Gtpase ◽  
Mapk Pathway ◽  
Mapk Signaling ◽  
Type I ◽  
Wild Type ◽  
Kit Ligand

Abstract p21-activated kinases (Paks) are downstream mediators of Rho GTPase proteins and have been implicated in yeast and immortalized cells as positive regulators of MAPK pathway members in modulating cell growth and cytoskeletal functions. However, their role in primary mammalian cells has not been described. NF1 encodes neurofibromin, which negatively regulates p21Ras activity by stimulating its intrinsic GTPase activity, and accelerating hydrolysis of Ras from the GTP to the GDP confirmation. Disruption of the NF1 locus results in neurofibromatosis type I (NF1), an inherited disorder characterized by the development of neurofibromas that contain large numbers of degranulating mast cells that have been implicated in tumor progression. Utilizing a genetic intercross of Pak 1−/− mice with mice haploinsufficient at the Nf1 locus, we studied the role of Pak1 in the context of normal and hyperactivated Ras-MAPK signaling in primary inflammatory mast cells. Pak1 was found to directly contribute to Ras-dependent signaling by modulating both Raf-1, Mek-1 and ERK1/2 activation. Loss of Pak1 fully corrects the hyperphosphorylation of ERK1/2 found in Nf1+/− mast cells to that of wild type controls. Deletion of Pak1 in Nf1+/− mast cells is associated with a correction of Kit ligand mediated proliferation to wild type levels in vitro. Further, after subcutaneous administration of Kit ligand via micro osmotic pumps, which is an established model that stimulates local proliferation of mast cells in vivo (Ingram, JEM 2001), we confirmed that genetic disruption of Pak1 corrects the proliferation of Nf1+/− mast cells in vivo to that of wild type controls. These data provide direct genetic evidence that Pak1 modulates the Ras-Raf-Mek-Erk pathway and identifies a specific molecular target within the inflammatory tumor microenvironment for the treatment or prevention of neurofibromas.

scholarly journals Co-occurring PTPN11 and SOS1 gene mutations in Noonan syndrome: does this predict a more severe phenotype?

2010 ◽  
Vol 54 (8) ◽  
pp. 717-722 ◽  
Author(s):  
Amanda Salem Brasil ◽  
Alexsandra C. Malaquias ◽  
Luciana Turolla Wanderley ◽  
Chong Ae Kim ◽  
José Eduardo Krieger ◽  
...  
Keyword(s):  
Noonan Syndrome ◽  
Autosomal Dominant ◽  
Mapk Pathway ◽  
Direct Sequencing ◽  
Phenotypic Expression ◽  
Gene Mutations ◽  
Mapk Signaling ◽  
Severe Phenotype ◽  
Autosomal Dominant Disorder ◽  
Atypical Phenotype

Noonan syndrome (NS) is an autosomal dominant disorder, with variable phenotypic expression, characterized by short stature, facial dysmorphisms and heart disease. Different genes of the RAS/MAPK signaling pathway are responsible for the syndrome, the most common are: PTPN11, SOS1, RAF1, and KRAS. The objective of this study was to report a patient with Noonan syndrome presenting mutations in two genes of RAS/MAPK pathway in order to establish whether these mutations lead to a more severe expression of the phenotype. We used direct sequencing of the PTPN11, SOS1, RAF1, and KRAS genes. We have identified two described mutations in heterozygosity: p.N308D and p.R552G in the genes PTPN11 and SOS1, respectively. The patient has typical clinical features similar to the ones with NS and mutation in only one gene, even those with the same mutation identified in this patient. A more severe or atypical phenotype was not observed, suggesting that these mutations do not exhibit an additive effect.

RASopathies in multidisciplinary pediatric hospita

2020 ◽  
pp. 21-23
Author(s):  
Н.В. Журкова ◽  
Л.А. Гандаева ◽  
А.А. Пушков ◽  
Е.Н. Басаргина ◽  
А.В. Пахомов ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Noonan Syndrome ◽  
Mapk Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Costello Syndrome ◽  
Inherited Diseases ◽  
Cardiofaciocutaneous Syndrome ◽  
Genes Encoding ◽  
Mitogen Activated Protein ◽  
Anagen Hair

RAS-патии - группа наследственных заболеваний, возникающая вследствие нарушения регуляции функции RAS/MAPK внутриклеточных путей (Ras/mitogen-activated protein kinase). Суммарная частота заболеваний данной группы - 1 случай на 1000 новорожденных. Наиболее часто среди RAS-патий встречается синдром Нунан. В настоящее время описано 13 генов, мутации которых отвечают за развитие данного заболевания, включая ген SHOC2, ассоциированный с Нунан-подобным синдромом и измененной структурой волос (Noonan-like syndrome with loose anagen hair) и ген LZTR1, мутации в котором приводят к развитию синдрома Нунан, тип 2 с аутосомно-рецессивным типом наследования. RASopathies - group of inherited diseases, caused by mutations in genes, encoding components or regulators of the Ras/mitogen-activated protein kinase (MAPK) pathway. We identified 28 patients with inherited diseases from RASopathies: 61% - with Noonan syndrome, 14 % - with Cardiofaciocutaneous syndrome, 14% - with Costello syndrome - 11% - Noonan syndrome-like with loose anagen hair. Mutation c.770C>T, p.S257L in RAF1gene is most common in hypertrophic cardiomyopathy patients with Noonan syndrome. All patients with Noonan syndrome-like with loose anagen hair have mutation c.4A>G , p.S2G in SHOC2 gene.

scholarly journals A Patient with Noonan Syndrome with a KRAS Mutation Who Presented Severe Nerve Root Hypertrophy

2021 ◽  
pp. 108-118
Author(s):  
Yoshihito Ando ◽  
Mikio Sawada ◽  
Tadataka Kawakami ◽  
Mitsuya Morita ◽  
Yoko Aoki
Keyword(s):  
Intellectual Disability ◽  
Nerve Root ◽  
Noonan Syndrome ◽  
Mapk Pathway ◽  
Clinical Manifestations ◽  
Mapk Signaling ◽  
De Novo Mutation ◽  
Pulmonary Artery Stenosis ◽  
Molecular Abnormalities ◽  
Cfc Syndrome

We report a 45-year-old female with clinical features resembling Noonan syndrome (NS) who presented with significant nerve root hypertrophy. She was initially diagnosed with Charcot-Marie-Tooth disease because her gait disturbance gradually deteriorated and nerve conduction velocity was reduced. However, she did not carry a <i>PMP22</i> gene mutation. RASopathies are a group of phenotypically overlapping developmental syndromes caused by germline mutations that encode components of the Ras/MAPK signaling pathway. These disorders include NS, cardiofaciocutaneous (CFC) syndrome, and Costello syndrome and are associated with molecular abnormalities in the Ras/MAPK pathway. The patient was suspected to have NS and related disorders because of pulmonary artery stenosis, lymphedema, distinctive facial appearance, and intellectual disability. Genetic analysis identified a heterozygous de novo mutation in <i>KRAS</i> (c.211T&#x3e;G, p.Tyr71Asp), which is usually observed in patients with NS or CFC syndrome. Although our patient was diagnosed with NS, she revealed clinical manifestations that were typical to CFC syndrome, including intellectual disability. It has been reported that some patients diagnosed with RASopathies with mutations in <i>PTPN11</i>, <i>SOS1</i>, or <i>KRAS</i> developed nerve root hypertrophy. These results suggest that nerve root hypertrophy may be associated with RASopathy, although the onset mechanisms of nerve root hypertrophy are unknown.

scholarly journals MEK inhibition ameliorates social behavior phenotypes in a Spred1 knockout mouse model for RASopathy disorders

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Sarah C. Borrie ◽  
Ellen Plasschaert ◽  
Zsuzsanna Callaerts-Vegh ◽  
Akihiko Yoshimura ◽  
Rudi D’Hooge ◽  
...  
Keyword(s):  
Social Behavior ◽  
Mouse Model ◽  
Social Dominance ◽  
Mapk Pathway ◽  
Mek Inhibitor ◽  
Mapk Signaling ◽  
Autism Spectrum ◽  
Nesting Behavior ◽  
Loss Of Function ◽  
Legius Syndrome

Abstract Background RASopathies are a group of disorders that result from mutations in genes coding for proteins involved in regulating the Ras-MAPK signaling pathway, and have an increased incidence of autism spectrum disorder (ASD). Legius syndrome is a rare RASopathy caused by loss-of-function mutations in the SPRED1 gene. The patient phenotype is similar to, but milder than, Neurofibromatosis type 1—another RASopathy caused by loss-of-function mutations in the NF1 gene. RASopathies exhibit increased activation of Ras-MAPK signaling and commonly manifest with cognitive impairments and ASD. Here, we investigated if a Spred1-/- mouse model for Legius syndrome recapitulates ASD-like symptoms, and whether targeting the Ras-MAPK pathway has therapeutic potential in this RASopathy mouse model. Methods We investigated social and communicative behaviors in Spred1-/- mice and probed therapeutic mechanisms underlying the observed behavioral phenotypes by pharmacological targeting of the Ras-MAPK pathway with the MEK inhibitor PD325901. Results Spred1-/- mice have robust increases in social dominance in the automated tube test and reduced adult ultrasonic vocalizations during social communication. Neonatal ultrasonic vocalization was also altered, with significant differences in spectral properties. Spred1-/- mice also exhibit impaired nesting behavior. Acute MEK inhibitor treatment in adulthood with PD325901 reversed the enhanced social dominance in Spred1-/- mice to normal levels, and improved nesting behavior in adult Spred1-/- mice. Limitations This study used an acute treatment protocol to administer the drug. It is not known what the effects of longer-term treatment would be on behavior. Further studies titrating the lowest dose of this drug that is required to alter Spred1-/- social behavior are still required. Finally, our findings are in a homozygous mouse model, whereas patients carry heterozygous mutations. These factors should be considered before any translational conclusions are drawn. Conclusions These results demonstrate for the first time that social behavior phenotypes in a mouse model for RASopathies (Spred1-/-) can be acutely reversed. This highlights a key role for Ras-MAPK dysregulation in mediating social behavior phenotypes in mouse models for ASD, suggesting that proper regulation of Ras-MAPK signaling is important for social behavior.

scholarly journals Co-inhibition of SMAD and MAPK signaling enhances 124I update in BRAF-mutant thyroid cancers

2021 ◽  
Author(s):  
Kathleen A. Luckett ◽  
Jennifer R. Cracchiolo ◽  
Gnana P. Krishnamoorthy ◽  
Luis Javier Leandro-Garcia ◽  
James Nagarajah ◽  
...  
Keyword(s):  
Mapk Pathway ◽  
Mek Inhibitor ◽  
Mapk Signaling ◽  
Type I ◽  
Iodide Uptake ◽  
Mapk Activation ◽  
Thyroid Cancers ◽  
Thyroid Hormone Biosynthesis ◽  
Braf Mutant

Constitutive MAPK activation silences genes required for iodide uptake and thyroid hormone biosynthesis in thyroid follicular cells. Accordingly, most BRAFV600E papillary thyroid cancers (PTC) are refractory to radioiodide (RAI) therapy. MAPK pathway inhibitors rescue thyroid differentiated properties and RAI responsiveness in mice and patient subsets with BRAFV600E-mutant PTC. TGFβ also impairs thyroid differentiation and has been proposed to mediate the effects of mutant BRAF. We generated a mouse model of Braf-PTC with thyroid-specific knockout of the TgfβR1 gene to investigate the role of TGFβ on thyroid differentiated gene expression and RAI uptake in vivo. Despite appropriate loss of TgfβR1, pSmad levels remained high, indicating that ligands other than TGFβ1 were engaging this pathway. The activin ligand subunits Inhba and Inhbb were found to be overexpressed in BrafV600E mutant thyroid cancers. Treatment with follistatin, a potent inhibitor of activin, or vactosertib, which inhibits both TGFβR1 and the activin type I receptor ALK4, induced a profound inhibition of pSMAD in BrafV600E-PTCs. Blocking SMAD signaling alone was insufficient to enhance iodide uptake in the setting of constitutive MAPK activation. However, combination treatment with either follistatin or vactosertib and the MEK inhibitor CKI increased 124I uptake compared to CKI alone. In summary, activin family ligands converge to induce pSMAD in Braf-mutant PTCs. Dedifferentiation of BrafV600E-PTCs cannot be ascribed primarily to activation of SMAD. However, targeting Tgfβ/activin-induced pSMAD augmented MAPK inhibitor effects on iodine incorporation into BRAF tumor cells, indicating that these two pathways exert interdependent effects on the differentiation state of thyroid cancer cells.

scholarly journals RARE-55. RIT1 MUTATION ASSOCIATED WITH SPINAL NEUROFIBROMATOSIS

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi233-vi233
Author(s):  
Mark Anderson ◽  
Nawal Shaikh ◽  
Eugene Long ◽  
Joseph Maher
Keyword(s):  
Noonan Syndrome ◽  
Mapk Pathway ◽  
Genetic Disorders ◽  
Neurofibromatosis Type ◽  
African American Female ◽  
Ras Pathway ◽  
Nerve Sheath Tumors ◽  
Café Au Lait Spots ◽  
History Of

Abstract Neurofibromatosis type 1 is defined clinically and molecularly by the presence of a mutation in neurofibromin, resulting in typical cutaneous, peripheral nerve and nerve root neurofibromas through the changes in regulation of the RAS pathway. A 33-year-old right-handed African-American female presented with a complaint of back pain, radiating down the legs and arms worsening over several years. On physical exam, the patient had no cutaneous neurofibromas, café-au-lait spots, or axillary freckling. MRI spine revealed diffuse symmetric fusiform nerve sheath tumors throughout the cervical, thoracic, and lumbar spine favored to represent neurofibromatosis. Genetics evaluation with pedigree revealed no family history of genetic disorders. Genetic testing was positive solely for a c.293A >G transition in exon 5 of the RIT1 gene, previously reported as a cause of the RASopathy Noonan syndrome, type-8. RASopathies are conditions caused by mutations in the proteins of the RAS-MAPK pathway. Noonan Syndrome can present with some combination of abnormalities of the ears, webbing of the neck, developmental delay, and cardiac abnormalities. This patient was without external phenotypic characteristics of Noonan Syndrome, yet was found to have a mutation in this pathway. RIT1 mutation has been previously described rarely with glioma development. Alternate mutations in the RAS-MAPK pathway should be considered in the differential for patients with spinal neurofibromatosis when typical neurofibromatosis mutations are absent.

scholarly journals Inherited Disorders of the Ras-MAPK Pathway

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. SCI-41-SCI-41
Author(s):  
Christian P. Kratz ◽  
Martin Zenker
Keyword(s):  
Cancer Risk ◽  
Noonan Syndrome ◽  
Conflicts Of Interest ◽  
Mapk Pathway ◽  
Heart Defects ◽  
Mapk Signaling ◽  
Juvenile Myelomonocytic Leukemia ◽  
Costello Syndrome ◽  
Inherited Disorders ◽  
Congenital Diseases

Abstract RASopathies are a group of rare congenital diseases in which dysregulated signaling through the RAS-MAPK signaling cases is the critical pathogenetic mechanism. This definition excludes postnatally acquired conditions (e.g. RAS-MAPK driven neoplasms) and PIK3-AKT pathway related disorders as well as conditions with only ancillary RAS pathway involvement (e.g. KAT6B-, RAP1A/B-related disorders). The definition, however, includes the following categories: (1) Noonan syndrome and related disorders, specifically Noonan syndrome (NS), NS with multiple lentigines, NS-like disorder with loose anagen hair, CBL syndrome, cardiofaciocutaneous syndrome, and Costello syndrome); (2) Neurofibromatosis type 1 and the related disorders Neurofibromatosis-Noonan syndrome and Legius syndrome; (3) Mosaic RASopathies including a rapidly growing group of mainly (neuro)cutaneous disorders with "oncogenic" mutations in a somatic mosaic state; (4) RAS-MAPK pathway dysregulation without a NS-like phenotype including non-syndromic intellectual disability due to SYNGAP1mutations and capillary malformation-arteriovenous malformation/Parkes-Weber syndrome; (5) RAS-MAPK pathway defects without overactivation such as metachondromatosis. Germline mutations leading to Ras-MAPK dysregulation typically lead to a characteristic pattern of craniofacial anomalies, heart defects, shorts stature, and variable neurodevelopmental deficits as seen in NS and other RASopathies of category 1. Confirmed genes leading to RASopathies from this category include BRAF,CBL, HRAS, KRAS, MAP2K1, MAP2K1, NRAS, PTPN11, RAF1, RIT1, SHOC2, SOS1, LZTR1, and PPP1CB. Newer genes include SOS2, MRAS, RRAS, and RASA2. For some individual RASopathy disease entities, specific genotype associations exist, for others, this correlation is not tight. The cancer risk in many patients with RASopathies is only moderately increased, however, for a subgroup of patients the cancer risk is very high. These include patients with Costello syndrome (HRAS) who develop rhabdomyosarcoma, neuroblastoma and bladder cancer, patients with NF1 who develop juvenile myelomonocytic leukemia (JMML), neurofibroma/-fibrosarcoma, and brain tumors, and patients and with CBL syndrome who develop JMML. New clinical studies explore the use of RAS-MAPK Pathway inhibitors in this unique population. Various animal and in vitro models have been described, which (partially) recapitulate the human RASopathy phenotype and phenotypic rescue by manipulating RAS-MAPK signal flow has been demonstrated. Disclosures No relevant conflicts of interest to declare.

Activating MRAS mutations cause Noonan syndrome associated with hypertrophic cardiomyopathy

2019 ◽  
Vol 29 (11) ◽  
pp. 1772-1783 ◽  
Author(s):  
Marialetizia Motta ◽  
Lena Sagi-Dain ◽  
Oliver H F Krumbach ◽  
Andreas Hahn ◽  
Amir Peleg ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Noonan Syndrome ◽  
De Novo ◽  
Mapk Pathway ◽  
Mapk Signaling ◽  
Ras Signaling ◽  
Genetic Syndromes ◽  
Activating Mutations ◽  
High Level ◽  
Functional Analyses

Abstract The RASopathies are a group of genetic syndromes caused by upregulated RAS signaling. Noonan syndrome (NS), the most common entity among the RASopathies, is characterized mainly by short stature, cardiac anomalies and distinctive facial features. Mutations in multiple RAS-MAPK pathway-related genes have been associated with NS and related phenotypes. We describe two unrelated patients presenting with hypertrophic cardiomyopathy (HCM) and dysmorphic features suggestive of NS. One of them died in the neonatal period because of cardiac failure. Targeted sequencing revealed de novo MRAS variants, c.203C &gt; T (p.Thr68Ile) and c.67G &gt; C (p.Gly23Arg) as causative events. MRAS has only recently been related to NS based on the observation of two unrelated affected individuals with de novo variants involving the same codons here found mutated. Gly23 and Thr68 are highly conserved residues, and the corresponding codons are known hotspots for RASopathy-associated mutations in other RAS proteins. Functional analyses documented high level of activation of MRAS mutants due to impaired GTPase activity, which was associated with constitutive plasma membrane targeting, prolonged localization in non-raft microdomains, enhanced binding to PPP1CB and SHOC2 protein, and variably increased MAPK and PI3K-AKT activation. This report provides additional evidence that a narrow spectrum of activating mutations in MRAS represents another rare cause of NS, and that MRAS has to be counted among the RASopathy genes predisposing to HCM. Moreover, our findings further emphasize the relevance of the MRAS-SHOC2-PPP1CB axis in the control of MAPK signaling, and the contribution of both MAPK and PI3K-AKT pathways in MRAS functional upregulation.

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