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 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 A de novo variant in CASK gene causing intellectual disability and brain hypoplasia: A Case Report and Literature Review

2021 ◽  
Author(s):  
Ying Zhang ◽  
Yanyan Nie ◽  
Yu Mu ◽  
Jie Zheng ◽  
Xiaowei Xu ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Mental Disorders ◽  
De Novo ◽  
Clinical Symptoms ◽  
Clinical Manifestations ◽  
De Novo Mutation ◽  
Loss Of Function ◽  
Bioinformatics Analyses ◽  
Whole Exome ◽  
De Novo Variant

Abstract Background：The pathogenic variation of CASK gene can cause CASK related mental disorders. The main clinical manifestations are microcephaly with pontine and cerebellar hypoplasia, X-linked mental disorders with or without nystagmus and FG syndrome. The main pathogenic mechanism is the loss of function of related protein caused by mutation. We reported a Chinese male newborn with a de novo variant in CASK gene. Case presentation：We present an 18-day-old baby with intellectual disability and brain hypoplasia. Whole-exome sequencing was performed, which detected a hemizygous missense mutation c.764G>A of CASK gene. The mutation changed the 255th amino acid from Arg to His. Software based bioinformatics analyses were conducted to infer its functional effect.Conclusions：In this paper, a de novo mutation of CASK gene was reported. Moreover, a detailed description of all the cases described in the literature is reported.CASK mutations cause a variety of clinical phenotypes. Its diagnosis is difficult due to the lack of typical clinical symptoms. Genetic testing should be performed as early as possible if this disease is suspected. This case provides an important reference for the diagnosis and treatment of future cases.

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.

scholarly journals Clinical manifestations in patients with SOS1 mutations range from Noonan syndrome to CFC syndrome

2008 ◽  
Vol 53 (9) ◽  
pp. 834-841 ◽  
Author(s):  
Yoko Narumi ◽  
Yoko Aoki ◽  
Tetsuya Niihori ◽  
Masahiro Sakurai ◽  
Hélène Cavé ◽  
...  
Keyword(s):  
Noonan Syndrome ◽  
Clinical Manifestations ◽  
Cfc Syndrome

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.

scholarly journals Brassinin Inhibits Proliferation in Human Liver Cancer Cells via Mitochondrial Dysfunction

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 332
Author(s):  
Taeyeon Hong ◽  
Jiyeon Ham ◽  
Jisoo Song ◽  
Gwonhwa Song ◽  
Whasun Lim
Keyword(s):  
Mitochondrial Dysfunction ◽  
Cancer Cells ◽  
Cell Lines ◽  
Mapk Pathway ◽  
Mapk Signaling ◽  
Nuclear Antigen ◽  
Cruciferous Vegetable ◽  
Antiproliferative Effects ◽  
Hep3b Cells ◽  
Human Liver Cancer Cells

Brassinin is a phytochemical derived from Chinese cabbage, a cruciferous vegetable. Brassinin has shown anticancer effects on prostate and colon cancer cells, among others. However, its mechanisms and effects on hepatocellular carcinoma (HCC) have not been elucidated yet. Our results confirmed that brassinin exerted antiproliferative effects by reducing proliferating cell nuclear antigen (PCNA) activity, a proliferation indicator and inducing cell cycle arrest in human HCC (Huh7 and Hep3B) cells. Brassinin also increased mitochondrial Ca2+ levels and depolarized the mitochondrial membrane in both Huh7 and Hep3B cells. Moreover, brassinin generated high amounts of reactive oxygen species (ROS) in both cell lines. The ROS scavenger N-acetyl-L-cysteine (NAC) inhibited this brassinin-induced ROS production. Brassinin also regulated the AKT and mitogen-activated protein kinases (MAPK) signaling pathways in Huh7 and Hep3B cells. Furthermore, co-administering brassinin and pharmacological inhibitors for JNK, ERK1/2 and P38 decreased cell proliferation in both HCC cell lines more than the pharmacological inhibitors alone. Collectively, our results demonstrated that brassinin exerts antiproliferative effects via mitochondrial dysfunction and MAPK pathway regulation on HCC cells.

scholarly journals Antimetastatic Effects of Sesamin on Human Head and Neck Squamous Cell Carcinoma through Regulation of Matrix Metalloproteinase-2

Molecules ◽  
2020 ◽  
Vol 25 (9) ◽  
pp. 2248 ◽  
Author(s):  
Jian-Ming Chen ◽  
Pei-Yin Chen ◽  
Chia-Chieh Lin ◽  
Ming-Chang Hsieh ◽  
Jen-Tsun Lin
Keyword(s):  
Oral Cancer ◽  
Matrix Metalloproteinase ◽  
Head And Neck ◽  
Mapk Pathway ◽  
Human Head ◽  
Mapk Signaling ◽  
Matrix Metalloproteinase 2 ◽  
Migration And Invasion ◽  
Dependent Manner

Background: Sesamin is a lignin present in sesame oil from the bark of Zanthoxylum spp. Sesamin reportedly has anticarcinogenic potential and exerts anti-inflammatory effects on several tumors. Hypothesis/Purpose: However, the effect of sesamin on metastatic progression in human head and neck squamous carcinoma (HNSCC) remains unknown in vitro and in vivo; hence, we investigated the effect of sesamin on HNSCC cells in vitro. Methods and Results: Sesamin-treated human oral cancer cell lines FaDu, HSC-3, and Ca9-22 were subjected to a wound-healing assay. Furthermore, Western blotting was performed to assess the effect of sesamin on the expression levels of matrix metalloproteinase (MMP)-2 and proteins of the MAPK signaling pathway, including p-ERK1/2, P-p38, and p-JNK1/2. In addition, we investigated the association between MMP-2 expression and the MAPK pathway in sesamin-treated oral cancer cells. Sesamin inhibited cell migration and invasion in FaDu, Ca9-22, and HSC-3 cells and suppressed MMP-2 at noncytotoxic concentrations (0 to 40 μM). Furthermore, sesamin significantly reduced p38 MAPK and JNK phosphorylation in a dose-dependent manner in FaDu and HSC-3 cells. Conclusions: These results indicate that sesamin suppresses the migration and invasion of HNSCC cells by regulating MMP-2 and is thus a potential antimetastatic agent for treating HNSCC.

scholarly journals Refractory pleural effusion as a rare complication of pulmonary vascular stenosis induced by fibrosing mediastinitis: a case report and literature review

2021 ◽  
Vol 49 (5) ◽  
pp. 030006052110100
Author(s):  
Suqiao Yang ◽  
Jianfeng Wang ◽  
Jifeng Li ◽  
Kewu Huang ◽  
Yuanhua Yang
Keyword(s):  
Pleural Effusion ◽  
Rare Complication ◽  
Clinical Manifestations ◽  
Pulmonary Vein Stenosis ◽  
Pulmonary Artery Stenosis ◽  
Heart Catheterization ◽  
Tissue Mass ◽  
Fibrosing Mediastinitis ◽  
Extrinsic Compression ◽  
Left Pleural Effusion

Fibrosing mediastinitis (FM) is a progressive, life-threatening disease characterized by extrinsic compression of mediastinal bronchovascular structures, and the clinical manifestations largely depend upon the affected structures. Pleural effusion is rarely reported in patients with FM. We herein describe a 70-year-old man who presented with recurrent breathlessness and refractory left pleural effusion. He was misdiagnosed with and treated for tuberculous pleurisy for several months. Thoracentesis revealed a transudative pleural effusion, and a contrast-enhanced computed tomography scan of the thorax showed an extensive mediastinal soft tissue mass consistent with FM. Pulmonary angiography demonstrated pulmonary artery stenosis on the right side and pulmonary vein stenosis mainly on the left side. After measurement of the pulmonary arterial pressure by right heart catheterization, the patient was diagnosed with pulmonary hypertension associated with FM. He underwent balloon angioplasty and stent implantation of the stenosed pulmonary vessels, which led to long-term improvement in his breathlessness and pleural effusion. Our systematic review of the literature highlights that pleural effusion can be an uncommon complication of FM and requires careful etiological differentiation.

scholarly journals Epigenetic control of pheromone MAPK signaling determines sexual fecundity inCandida albicans

2017 ◽  
Vol 114 (52) ◽  
pp. 13780-13785 ◽  
Author(s):  
Christine M. Scaduto ◽  
Shail Kabrawala ◽  
Gregory J. Thomson ◽  
William Scheving ◽  
Andy Ly ◽  
...  
Keyword(s):  
Candida Albicans ◽  
G Protein ◽  
Map Kinases ◽  
Mapk Pathway ◽  
Cell Types ◽  
Mapk Signaling ◽  
Toggle Switch ◽  
Β Subunit ◽  
Epigenetic Control ◽  
Incandida Albicans

Several pathogenicCandidaspecies are capable of heritable and reversible switching between two epigenetic states, “white” and “opaque.” InCandida albicans, white cells are essentially sterile, whereas opaque cells are mating-proficient. Here, we interrogate the mechanism by which the white-opaque switch regulates sexual fecundity and identify four genes in the pheromone MAPK pathway that are expressed at significantly higher levels in opaque cells than in white cells. These genes encode the β subunit of the G-protein complex (STE4), the pheromone MAPK scaffold (CST5), and the two terminal MAP kinases (CEK1/CEK2). To define the contribution of each factor to mating,C. albicanswhite cells were reverse-engineered to express elevated, opaque-like levels of these factors, either singly or in combination. We show that white cells co-overexpressingSTE4,CST5, andCEK2undergo mating four orders of magnitude more efficiently than control white cells and at a frequency approaching that of opaque cells. Moreover, engineered white cells recapitulate the transcriptional and morphological responses of opaque cells to pheromone. These results therefore reveal multiple bottlenecks in pheromone MAPK signaling in white cells and that alleviation of these bottlenecks enables efficient mating by these “sterile” cell types. Taken together, our findings establish that differential expression of several MAPK factors underlies the epigenetic control of mating inC. albicans. We also discuss how fitness advantages could have driven the evolution of a toggle switch to regulate sexual reproduction in pathogenicCandidaspecies.

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