scholarly journals Imatinib, a New Adjuvant Medical Treatment for Multifocal Villonodular Synovitis Associated to Noonan Syndrome: A Case Report and Literature Review

2022 ◽  
Vol 8 ◽  
Author(s):  
Romain Dalla-Torre ◽  
Vincent Crenn ◽  
Pierre Menu ◽  
Bertrand Isidor ◽  
Pascale Guillot ◽  
...  
Keyword(s):  
Noonan Syndrome ◽  
Technical Assistance ◽  
Kinase Inhibitors ◽  
Mapk Pathway ◽  
Heart Defects ◽  
Mitogen Activated Protein Kinase ◽  
Villonodular Synovitis ◽  
Multisystem Disorder ◽  
First Case

Noonan syndrome (NS) is an autosomal dominant multisystem disorder caused by the dysregulation of the Rat Sarcoma/Mitogen-activated protein kinase (RAS/MAPK) pathway and characterized by short stature, heart defects, pectus excavatum, webbed neck, learning disabilities, cryptorchidism, and facial dysmorphia. Villonodular synovitis is a joint disorder most common in young adults characterized by an abnormal proliferation of the synovial membrane. Multifocal Villonodular synovitis is a rare disease whose recurrent nature can make its management particularly difficult. Currently, there is no systemic therapy recommended in diffuse and recurrent forms, especially because of the fear of long-term side effects in patients, who are usually young. Yet, tyrosine kinase inhibitors seem promising to reduce the effects of an aberrant colony stimulating factor-1 (CSF-1) production at the origin of the synovial nodule proliferation. We present here the case of a 21-year-old woman with NS associated to diffuse multifocal villonodular synovitis (DMVS). Our clinical case provides therapeutic experience in this very rare association. Indeed, in association with surgery, the patient improved considerably: she had complete daily life autonomy, knee joint amplitudes of 100° in flexion and 0° in extension and was able to walk for 10 min without any technical assistance. To our knowledge, this is the first case of a patient suffering from DMVS associated with a Noonan syndrome treated with Glivec® (oral administration at a dosage of 340 mg/m2 in children, until disease regression) on a long-term basis.

scholarly journals The first reported case of Noonan syndrome complicated with hepatocellular carcinoma.

2021 ◽  
Author(s):  
Satoru Kakizaki ◽  
Daisuke Uehara ◽  
Hiroki Tojima ◽  
Takayoshi Suga ◽  
Yuichi Yamazaki ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Congenital Heart Disease ◽  
Heart Disease ◽  
Noonan Syndrome ◽  
Congenital Heart ◽  
Mapk Pathway ◽  
Facial Features ◽  
Multisystem Disorder ◽  
First Case ◽  
Genes Encoding

Noonan syndrome is a genetic multisystem disorder characterized by distinctive facial features, developmental delay, congenital heart disease, and other conditions. It is associated with mutation of genes encoding the proteins in the RAS-MAPK pathway, including PTPN11. We herein describe the first case of Noonan syndrome complicated with hepatocellular carcinoma.

scholarly journals Identification of RAS-Mitogen-Activated Protein Kinase Signaling Pathway Modulators in an ERF1 Redistribution® Screen

2006 ◽  
Vol 11 (4) ◽  
pp. 423-434 ◽  
Author(s):  
Charlotta Grånäs ◽  
Betina Kerstin Lundholt ◽  
Frosty Loechel ◽  
Hans-Christian Pedersen ◽  
Sara Petersen Bjørn ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Signaling Pathway ◽  
Kinase Inhibitors ◽  
Mapk Pathway ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein ◽  
A Cell ◽  
Protein Kinase Signaling

The RAS-mitogen-activated protein kinase (MAPK) signaling pathway has a central role in regulating the proliferation and survival of both normal and tumor cells. This pathway has been 1 focus area for the development of anticancer drugs, resulting in several compounds, primarily kinase inhibitors, in clinical testing. The authors have undertaken a cell-based, high-throughput screen using a novel ERF1 Redistribution® assay to identify compounds that modulate the signaling pathway. The hit compounds were subsequently tested for activity in a functional cell proliferation assay designed to selectively detect compounds inhibiting the proliferation of MAPK pathway-dependent cancer cells. The authors report the identification of 2 cell membrane-permeable compounds that exhibit activity in the ERF1 Redistribution® assay and selectively inhibit proliferation of MAPK pathway-dependent malignant melanoma cells at similar potencies (IC50 =< 5 μM). These compounds have drug-like structures and are negative in RAF, MEK, and ERK in vitro kinase assays. Drugs belonging to these compound classes may prove useful for treating cancers caused by excessive MAPK pathway signaling. The results also show that cell-based, high-content Redistribution® screens can detect compounds with different modes of action and reveal novel targets in a pathway known to be disease relevant.

scholarly journals LZTR1 is a regulator of RAS ubiquitination and signaling

Science ◽  
2018 ◽  
Vol 362 (6419) ◽  
pp. 1171-1177 ◽  
Author(s):  
Johannes W. Bigenzahn ◽  
Giovanna M. Collu ◽  
Felix Kartnig ◽  
Melanie Pieraks ◽  
Gregory I. Vladimer ◽  
...  
Keyword(s):  
Leucine Zipper ◽  
Kinase Inhibitors ◽  
Mapk Pathway ◽  
Resistance Mechanisms ◽  
Mitogen Activated Protein Kinase ◽  
Loss Of Function ◽  
Pathway Activation ◽  
Mitogen Activated Protein ◽  
Human Disorders ◽  
Ras Isoforms

In genetic screens aimed at understanding drug resistance mechanisms in chronic myeloid leukemia cells, inactivation of the cullin 3 adapter protein-encoding leucine zipper-like transcription regulator 1 (LZTR1) gene led to enhanced mitogen-activated protein kinase (MAPK) pathway activity and reduced sensitivity to tyrosine kinase inhibitors. Knockdown of theDrosophila LZTR1orthologCG3711resulted in a Ras-dependent gain-of-function phenotype. Endogenous human LZTR1 associates with the main RAS isoforms. Inactivation ofLZTR1led to decreased ubiquitination and enhanced plasma membrane localization of endogenous KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog). We propose that LZTR1 acts as a conserved regulator of RAS ubiquitination and MAPK pathway activation. BecauseLZTR1disease mutations failed to revert loss-of-function phenotypes, our findings provide a molecular rationale forLZTR1involvement in a variety of inherited and acquired human disorders.

scholarly journals Impaired Binding of 14-3-3 to C-RAF in Noonan Syndrome Suggests New Approaches in Diseases with Increased Ras Signaling

2010 ◽  
Vol 30 (19) ◽  
pp. 4698-4711 ◽  
Author(s):  
Manuela Molzan ◽  
Benjamin Schumacher ◽  
Corinna Ottmann ◽  
Angela Baljuls ◽  
Lisa Polzien ◽  
...  
Keyword(s):  
Protein Interaction ◽  
Noonan Syndrome ◽  
Developmental Disorders ◽  
Mapk Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Ras Signaling ◽  
Membrane Recruitment ◽  
Protein Protein Interaction ◽  
Binding Data ◽  
Mitogen Activated Protein

ABSTRACT The Ras-RAF-mitogen-activated protein kinase (Ras-RAF-MAPK) pathway is overactive in many cancers and in some developmental disorders. In one of those disorders, namely, Noonan syndrome, nine activating C-RAF mutations cluster around Ser259, a regulatory site for inhibition by 14-3-3 proteins. We show that these mutations impair binding of 14-3-3 proteins to C-RAF and alter its subcellular localization by promoting Ras-mediated plasma membrane recruitment of C-RAF. By presenting biophysical binding data, the 14-3-3/C-RAFpS259 crystal structure, and cellular analyses, we indicate a mechanistic link between a well-described human developmental disorder and the impairment of a 14-3-3/target protein interaction. As a broader implication of these findings, modulating the C-RAFSer259/14-3-3 protein-protein interaction with a stabilizing small molecule may yield a novel potential approach for treatment of diseases resulting from an overactive Ras-RAF-MAPK pathway.

scholarly journals Effectiveness of Planned Teaching on Knowledge Regarding Noonan Syndrome among Nursing Students

2021 ◽  
pp. 709-713
Author(s):  
Pragati Alnewar ◽  
Seema Singh ◽  
Vaishali Tembhare
Keyword(s):  
Nursing Students ◽  
Nursing Care ◽  
Noonan Syndrome ◽  
Mapk Pathway ◽  
Demographic Variable ◽  
Leadership Role ◽  
Research Approach ◽  
Knowledge Level ◽  
Multisystem Disorder ◽  
Post Test

Background: Noonan syndrome is a genetic multisystem disorder characterized by distinctive facial features, developmental delay, learning difficulties, short stature, congenital heart disease, renal anomalies, lymphatic malformation and bleeding difficulties, mutations that cause Noonan syndrome alter genes encoding proteins with roles in the RAS-MAPK pathway, leading to pathway dysregulation. estimated prevalence of Noonan syndrome 1 in 1000-2500. Nursing student having insufficient knowledge regarding Noonan syndrome most responders perceive serious deficiencies in their preparation to care such patients As genetic advances increasingly impact nursing care, nurses are expected to have necessary knowledge to interpret genetic and genomic information and technology with translation into nursing care. The aim of the study is to aware a future nurse for Noonan syndrome, carrying the role of counsellor, care manager and teacher for patient and their families’ nurses will have an opportunity to expand as well as to create new leadership role in health care. Therefore, the development of educational program for nursing knowledge is essential for future nurses. Objectives: To assess the existing knowledge level regarding Noonan Syndrome among Basic B.Sc. nursing students. To evaluate the effectiveness of planned teaching on knowledge regarding Noonan syndrome among Basic B.Sc. nursing students. To associate posttest knowledge score with selected demographic variable. Materials and Methods: A one group pre-test and post-test design was adopted to assess the existing knowledge level regarding Noonan Syndrome among Basic B.Sc. nursing students. In this study, evaluatory research approach will be used. convenient sampling technique will be used to collect data.  Pre-test will be conducted to assessed primarily for the existing knowledge level regarding Noonan Syndrome among Basic B.Sc. nursing students. And then planned teaching on Noonan syndrome will be given to selected sample by researcher as intervention. Post-test outcomes involve evaluation of effectiveness of planned teaching. Expected Results: This study is planned to assess the effectiveness of planned teaching on knowledge regarding Noonan syndrome among nursing students. Conducting planned teaching will be effective for improving knowledge of the respondents.

scholarly journals Orofacial Findings and Dental Management of Noonan Syndrome: A Case Report

2021 ◽  
Author(s):  
Razeem Khalid Alhassoun
Keyword(s):  
Case Report ◽  
Noonan Syndrome ◽  
Heart Defects ◽  
Treatment Plan ◽  
Mitogen Activated Protein Kinase ◽  
Palpebral Fissure ◽  
Class Iii ◽  
High Arched Palate ◽  
Dental Professional ◽  
Congenitally Missing

Noonan Syndrome (NS) is an autosomal dominant condition caused by mutations in multiple genes in the RAS-MAP (Mitogen-Activated Protein) Kinase pathway. It is typically characterised by short stature, broad webbed neck, abnormal chest shape, congenital heart defects and developmental delay. Oral manifestations include high arched palate, micrognathia, malocclusion, impacted teeth and jaw bones. Presented here is a case of NS in a 26-year-old female, reported to the dental clinic in College of Dentistry, Princess Nourah Bint Abdulrahman University. The cranio-dentofacial features of this syndrome can be diagnosed by the dentist and these features can be unrecognised by the physician. The dentofacial features of the patient included a broad forehead, down slanting palpebral fissure, flat base of the nose and low junction of the ears, prominent nasolabial folds, Class III molar malocclusion, edge-to-edge bite, high arched palate, and congenitally missing teeth. The present patient was first diagnosed by a dental professional and hence, this case report aims to present this syndrome from a dental viewpoint. The treatment plan was to improve her oral hygiene, retain the deciduous tooth and space maintainer in the congenitally missing tooth to preserve space for the future prosthodontic treatment.

Mechanisms of Resistance to Mitogen-Activated Protein Kinase Pathway Inhibition in BRAF-Mutant Melanoma

2012 ◽  
pp. 680-684 ◽  
Author(s):  
Eva M. Goetz ◽  
Levi A. Garraway
Keyword(s):  
Protein Kinase ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Mapk Pathway ◽  
Drug Binding ◽  
Mitogen Activated Protein Kinase ◽  
Braf V600e ◽  
Mechanisms Of Resistance ◽  
Mitogen Activated Protein

Overview: Anticancer drug resistance remains a crucial impediment to the care of many patients with cancer. Although the exact mechanisms of resistance may differ for each therapy, common mechanisms of resistance predominate, including drug inactivation or modification, mutation of the target protein, reduced drug accumulation, or bypass of target inhibition. With the discovery and use of targeted therapies (such as small-molecule kinase inhibitors), resistance has received renewed attention—especially in light of the dramatic responses that may emerge from such therapeutics in particular genetic or molecular contexts. Recently, the mitogen-activated protein kinase (MAPK) pathway has become exemplary in this regard, since it is activated in many different cancers. Drugs targeting RAF and MAPK kinase (MEK) are currently in clinical trials for the treatment of several types of cancer. Vemurafenib, a selective RAF kinase inhibitor recently approved for the treatment of BRAF(V600E) melanoma, shows strong efficacy initially; however, the development of resistance is nearly ubiquitous. In vitro testing and analysis of patient samples have uncovered several mechanisms of resistance to RAF inhibition. Surprisingly, mutations in the drug-binding pocket have not thus far been observed; however, other alterations at the level of RAF, as well as downstream activation of MEK and bypass of MEK/extracellular signal-regulated kinase (ERK) signaling altogether, confer resistance to vemurafenib. Looking forward, combined RAF and MEK inhibitor treatments may improve efficacy—yet we must anticipate mechanisms of resistance to this combination as well. Therefore, understanding and/or determining the mechanism of resistance are paramount to effective cancer treatment.

scholarly journals Lymphatic Abnormalities in Noonan Syndrome Spectrum Disorders: A Systematic Review

2021 ◽  
pp. 1-11
Author(s):  
Julia Sleutjes ◽  
Lotte Kleimeier ◽  
Erika Leenders ◽  
Willemijn Klein ◽  
Jos Draaisma
Keyword(s):  
Systematic Review ◽  
Noonan Syndrome ◽  
Mapk Pathway ◽  
Nuchal Translucency ◽  
Mitogen Activated Protein Kinase ◽  
Mapk Signalling Pathway ◽  
Lymphatic Abnormalities ◽  
Pathogenic Variants ◽  
Spectrum Disorders ◽  
Mapk Inhibitors

Noonan syndrome spectrum disorders are a group of phenotypically related conditions, resembling Noonan syndrome, caused by germline pathogenic variants in genes within the Ras/mitogen-activated protein kinase (Ras/MAPK) signalling pathway. Lymphatic dysplasia with a clinical lymphatic abnormality is one of the major features. We performed a systematic review to get more insight in (1) the prevalence of clinically lymphatic abnormalities in patients with a genetically proven Noonan syndrome spectrum disorder, (2) if a genotype-lymphatic phenotype relation can be found and describe the clinical presentation and course of the lymphatic abnormality. Most studies report patients with Noonan syndrome. Prenatally, the prevalence of increased nuchal translucency differs from 7% in patients with pathogenic <i>PTPN11</i> variant<i>s</i> to 38% in patients with pathogenic <i>RIT1</i> variants, and the prevalence of pleural effusions differed from 7% in patients with pathogenic <i>SOS1</i> to 29% in patients with pathogenic <i>RIT1</i> variants. Postnatally, the prevalence of lymphedema differs from 16% in patients with pathogenic <i>PTPN11</i> variants to 44% in patients with pathogenic <i>SOS1</i> variants, and the prevalence of acquired chylothorax is 4% in patients with pathogenic <i>RIT1</i> variants. Lymphatic abnormalities do occur in patients with cardiofaciocutaneous syndrome and Costello syndrome. In conclusion, Noonan syndrome spectrum disorders, Noonan syndrome in particular, are associated with lymphatic abnormalities. Combining the available published literature about genetically proven Noonan syndrome spectrum disorders, it appears likely that the lifetime prevalence of these abnormalities in Noonan syndrome is higher than the 20% that were generally accepted so far. This is increasingly important, because the activation of the RAS/MAPK pathway can be inhibited by RAS/MAPK inhibitors, and clinically severe lymphatic abnormalities may improve.

Abstract 397: Generation of Raf1 Mutant and Crispr-cas9 Corrected Isogenic iPSC-derived Cardiomyocytes to Model Hypertrophic Cardiomyopathy in Noonan Syndrome

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Fabrice Jaffré ◽  
Gang Wang ◽  
Amy Roberts ◽  
William Pu ◽  
Andreas Hahn ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Genome Editing ◽  
Noonan Syndrome ◽  
Molecular Mechanisms ◽  
Germ Line ◽  
Mapk Pathway ◽  
Heart Defects ◽  
Single Point ◽  
Cardiac Cells ◽  
Single Point Mutation

Background: Hypertrophic cardiomyopathy (HCM) is a major cause of death in infants and children. Noonan Syndrome (NS), an autosomal dominant RASopathy disorder, is characterized by multiple defects, including short stature, facial dysmorphia, and congenital heart defects that include HCM. RASopathies are caused by germ-line mutations that affect the canonical RAS-MAPK pathway. Indeed, 95% of NS patients with a mutation in Raf1 , a gene that plays an integral role in this signaling cascade, exhibit HCM. However, the molecular mechanisms that elicit HCM in these patients remain poorly understood. Objective: To generate human NS Raf1 induced-pluripotent stem cells (iPSCs), correct the mutation by genome editing and subsequently differentiate isogenic iPSC lines into cardiomyocytes to characterize the molecular and genetic basis of HCM in NS patients. Results: We generated iPSCs from skin fibroblasts obtained from a NS pediatric patient with a single point mutation in the Raf1 gene. Using electroporation of four episomal vectors containing the Yamanaka factors, we obtained several iPSC clones with normal karyotypes and strong expression of pluripotent markers (Nanog, Oct4, Lin28, Sox2) as detected by RT-qPCR and immunofluorescence. We next corrected the mutation in the NS Raf1 iPSCs using genome editing CRISPR-Cas9 nickase technology. Correction of the Raf1 mutation was determined at the clonal level by PCR followed by Restriction Fragment Length Polymorphism and confirmed by Sanger sequencing. In addition, by inducing a Cas9 nickase-dependent frame shift mutation we also generated an isogenic iPSC line where Raf1 gene was knockout (KO), as demonstrated at the RNA level by RT-qPCR and at the protein level by Western Blot. We next differentiated these multiple iPSC lines (mutant, corrected and KO) into isogenic beating cardiomyocytes, with more >98% of the cells positive for specific cardiomyocyte markers (α-actinin and cardiac TroponinT). Conclusion: We have successfully generated human NS Raf1 isogenic iPSC lines and corresponding cardiomyocytes. Currently, we are in progress of characterizing these cardiac cells to determine the molecular basis of NS-dependent HCM. Ultimately, our work should reveal new targets to treat HCM in NS patients.

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.

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