932 results on '"rasopathy"'
Search Results
2. Clinical features and molecular genetics of patients with RASopathies: expanding the phenotype with rare genes and novel variants.
- Author
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Yılmaz Uzman, Ceren, Gürsoy, Semra, Özkan, Behzat, Vuran, Gamze, Ayyıldız Emecen, Durdugül, Köprülü, Özge, Bilen, Mertkan Mustafa, and Hazan, Filiz
- Abstract
The RASopathies are a group of disorders resulting from a germline variant in the genes encoding the Ras/mitogen-activated protein kinase pathway. These disorders include Noonan syndrome (NS), cardiofaciocutaneous syndrome (CFC), Costello syndrome (CS), Legius syndrome (LS), and neurofibromatosis type 1 (NF1), and have overlapping clinical features due to RAS/MAPK dysfunction. In this study, we aimed to describe the clinical and molecular features of patients exhibiting phenotypic manifestations consistent with RASopathies. The study included 149 patients from 146 unrelated families who were admitted between 2019 and 2023 with a clinical suspicion of RASopathy spectrum disorder. Clinical and laboratory characteristics of the patients at the time of the diagnosis were obtained from hospital records. Variant analysis of twenty-four RASopathy genes was performed using a targeted next-generation sequencing (NGS) panel, and the variants were classified according to American College of Medical Genetics and Genomics Standards and Guidelines recommendations. Pathogenic/likely pathogenic variants were detected in 39 out of 149 patients (26.1%). Thirty-two patients were diagnosed as NS (32/39; 82%). The variants detected in NS patients were PTPN11 (21/32; 65.6%), LZTR1 (3/32; 9.3%), SOS1 (2/32; 6.2%), RAF1 (2/32; 6.2%), RIT1 (2/32; 6.2%), KRAS (1/32; 3.1%), and RRAS (1/32; 3.1%) genes, respectively. The remaining patients were diagnosed with CS (2/39; 5.1%), NF1 (2/39; 5.1%), NF-NS (2/39; 5.1%), and CFC (1/39; 2.5%). We observed rare clinical findings including lymphangioma circumscriptum, Meckel’s diverticulum, and omphalocele in three patients with PTPN11 gene variations. Additionally, we detected corpus callosum thickness in a patient with the SOS1 gene variant, which has not been previously described in NS. We also identified three novel variants in RIT1, BRAF, and NF1 genes. Conclusion: In this study, we described rare clinical manifestations and detected three novel variants in NF1, BRAF, and RIT1 genes. We propose that NGS technology enables the detection of variants in rare genes responsible for the etiology of RASopathies. The study, therefore, not only contributes to the existing literature but also expands the spectrum of genotype and phenotype of RASopathies. What is Known: • RASopathies are a group of disorders caused by germline variants in genes involved in the Ras/mitogen-activated protein kinase (RAS/MAPK) pathway. • These disorders, including Noonan syndrome (NS), Cardiofaciocutaneous syndrome (CFC), Costello syndrome (CS), Legius syndrome, and Neurofibromatosis type 1 (NF1), share overlapping clinical features due to RAS/MAPK dysfunction. Molecular diagnosis of RASopathies is crucial for understanding the genetic basis and guiding clinical management, although the phenotype-genotype relationships remain incompletely defined. What is New: • This study provides new insights into the molecular and clinical characteristics of RASopathies by examining 149 patients from 146 families, with a focus on the genetic variants found in 24 RASopathy-related genes. Three novel variants were identified in the RIT1, BRAF, and NF1 genes, expanding the genetic spectrum of RASopathies. • Additionally, rare clinical findings, such as lymphangioma circumscriptum and corpus callosum thickness, were reported in patients with PTPN11 and SOS1 gene variations, respectively. These observations contribute new phenotypic data to the existing body of knowledge. [ABSTRACT FROM AUTHOR] more...
- Published
- 2025
- Full Text
- View/download PDF
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3. Recurrent p.H119Y variant in MAP2K1 expands the phenotypic spectrum of MAP2K1‐related RASopathy.
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Grange, Dorothy K., Wegner, Daniel J., Wambach, Jennifer A., Sisco, Kathleen A., Stone, Stephen I., Sheehan, Jonathan H., Ramsey, Keri M., Narayanan, Vinodh, Rauen, Katherine A., and Cole, F. Sessions more...
- Abstract
We report three unrelated individuals with atypical clinical findings for cardio‐facio‐cutaneous (CFC) syndrome, all of whom have the same novel, heterozygous de novo p.H119Y (c.355 C>T) transition variant in MAP2K1, identified by exome sequencing. MAP2K1 encodes MEK1, dual specificity mitogen‐activated protein kinase kinase 1, and is one of four genes in the canonical RAS/MAPK signal transduction pathway associated with CFC syndrome. The p.H119Y variant is a non‐conservative amino acid substitution that is predicted to impact the tertiary protein structure, and it occurs at a position in the protein kinase domain of MAP2K1 that is highly conserved across species. The clinical findings in these three individuals include facial features that are nonclassical for CFC syndrome, extremely poor weight gain, absence of congenital cardiac defects or cardiomyopathy, normal cognition or only mild intellectual disabilities, normal hair, mild skin abnormalities, and consistent behavioral features of anxiety, photophobia, and sensory hypersensitivities. These individuals expand the phenotypic spectrum of MAP2K1‐related RASopathy. [ABSTRACT FROM AUTHOR] more...
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- 2025
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4. Case report: MEK inhibitor as treatment for multi-lineage mosaic KRAS G12D-associated epidermal nevus syndrome in a pediatric patient.
- Author
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Dionysiou, Margarita, Makri, Stavriani C., Ahlawat, Shivani, Guryildirim, Melike, Barañano, Kristin W., Groves, Mari L., Argani, Pedram, and Pratilas, Christine A.
- Subjects
SPINAL nerve roots ,MITOGEN-activated protein kinases ,CHILD patients ,NOONAN syndrome ,PSEUDOPOTENTIAL method - Abstract
The RASopathies, collectively, are a spectrum of genetic syndromes caused by mutations in genes involved in the RAS/ mitogen-activated protein kinase (MAPK) pathway, including but not limited to PTPN11 , NRAS , KRAS , HRAS , BRAF , and MAP2K1. Recognized RASopathy conditions include neurofibromatosis type 1 (NF1), Noonan syndrome, capillary malformation-arteriovenous malformation syndrome, Costello syndrome, cardiofacio-cutaneous (CFC) syndrome, LEOPARD syndrome and Legius syndrome. The RASopathies often display overlapping clinical features, presumably owing to common RAS-MAPK signaling pathway activation driving dysregulated cell proliferation. Epidermal nevus syndromes (ENS) are described as the presence of epidermal nevi, in individuals also affected by extra-cutaneous organ system involvement, and there is recent recognition of mosaic RAS mutations as molecular drivers of ENS. Currently, no curative treatments exist for RASopathy driven conditions, but rather symptom-directed management is the currently accepted standard. Here, we detail a unique case of a child exhibiting diffuse spinal nerve root hypertrophy in the context of epidermal nevus syndrome driven by molecularly confirmed KRAS G12D mosaicism, treated with the MEK 1/2 inhibitor selumetinib. Herein, we report the response of this patient to targeted therapy of more than two years' duration, including stabilization of multilevel nerve root hypertrophy as well as significant improvement in epidermal nevi. While the effectiveness of MEK inhibitors such as selumetinib is established in NF1 -associated inoperable plexiform neurofibromas, their use in managing hyperactive KRAS -driven epidermal nevi and hypertrophic neuropathy remains unproven, and this case, to our knowledge, is the first such case to be reported. Shared molecular dysregulation and overlapping clinical features between these conditions suggest potential for effective therapeutic application of MEK directed therapy to address a range of conditions resulting from germline and/ or mosaic expression of aberrantly regulated RAS signaling. [ABSTRACT FROM AUTHOR] more...
- Published
- 2024
- Full Text
- View/download PDF
5. Noonan syndrome‐like phenotype associated with an ERF frameshift variant.
- Author
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Hirano, Yasuhiro, Kuroda, Yukiko, Enomoto, Yumi, Naruto, Takuya, Muroya, Koji, and Kurosawa, Kenji
- Abstract
Noonan syndrome is a so‐called "RASopathy," that is characterized by short stature, distinctive facial features, congenital heart defects, and developmental delay. Of individuals with a clinical diagnosis of Noonan syndrome, 80%–90% have pathogenic variants in the known genes implicated in the disorder, but the molecular mechanism is unknown in the remaining cases. Heterozygous pathogenic variants of ETS2 repressor factor (ERF), which functions as a repressor in the RAS/MAPK signaling pathway, cause syndromic craniosynostosis. Here, we report an ERF frameshift variant cosegregating with a Noonan syndrome‐like phenotype in a family. The proband was a 3‐year‐old female who presented with dysmorphic facial features, including proptosis, hypertelorism, slightly down slanted palpebral fissures, low‐set posteriorly rotated ears, depressed nasal bridge, short stature, and developmental delay. Exome sequencing of the proband identified a heterozygous ERF variant [NM_006494.4: c.185del p.(Glu62Glyfs*15)]. Her mother and sister showed a similar phenotype and had the same heterozygous ERF variant. A large proportion of the previously reported patients with syndromic craniosynostosis and pathogenic ERF variants also showed characteristic features that overlap with those of Noonan syndrome. The present finding supports an association between heterozygous ERF variants and a Noonan syndrome‐like phenotype. [ABSTRACT FROM AUTHOR] more...
- Published
- 2024
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6. The ribosomal S6 kinase 2 (RSK2)–SPRED2 complex regulates the phosphorylation of RSK substrates and MAPK signaling
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Lopez, Jocelyne, Bonsor, Daniel A, Sale, Matthew J, Urisman, Anatoly, Mehalko, Jennifer L, Cabanski-Dunning, Miranda, Castel, Pau, Simanshu, Dhirendra K, and McCormick, Frank
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Cancer ,2.1 Biological and endogenous factors ,1.1 Normal biological development and functioning ,Generic health relevance ,Mitogen-Activated Protein Kinases ,Phosphorylation ,Ribosomal Protein S6 Kinases ,90-kDa ,Signal Transduction ,Humans ,Cell Line ,Protein Domains ,Repressor Proteins ,Gene Knockdown Techniques ,Protein Transport ,Protein Binding ,Protein Structure ,Tertiary ,Models ,Molecular ,Neurofibromin 1 ,RAS signaling ,RASopathy ,RSK2 ,SPRED2 ,kinase ,neurofibromin ,Chemical Sciences ,Medical and Health Sciences ,Biochemistry & Molecular Biology ,Biological sciences ,Biomedical and clinical sciences ,Chemical sciences - Abstract
Sprouty-related EVH-1 domain-containing (SPRED) proteins are a family of proteins that negatively regulate the RAS-Mitogen-Activated Protein Kinase (MAPK) pathway, which is involved in the regulation of the mitogenic response and cell proliferation. However, the mechanism by which these proteins affect RAS-MAPK signaling has not been elucidated. Patients with mutations in SPRED give rise to unique disease phenotypes; thus, we hypothesized that distinct interactions across SPRED proteins may account for alternative nodes of regulation. To characterize the SPRED interactome and evaluate how members of the SPRED family function through unique binding partners, we performed affinity purification mass spectrometry. We identified 90-kDa ribosomal S6 kinase 2 (RSK2) as a specific interactor of SPRED2 but not SPRED1 or SPRED3. We identified that the N-terminal kinase domain of RSK2 mediates the interaction between amino acids 123 to 201 of SPRED2. Using X-ray crystallography, we determined the structure of the SPRED2-RSK2 complex and identified the SPRED2 motif, F145A, as critical for interaction. We found that the formation of this interaction is regulated by MAPK signaling events. We also find that this interaction between SPRED2 and RSK2 has functional consequences, whereby the knockdown of SPRED2 resulted in increased phosphorylation of RSK substrates, YB1 and CREB. Furthermore, SPRED2 knockdown hindered phospho-RSK membrane and nuclear subcellular localization. We report that disruption of the SPRED2-RSK complex has effects on RAS-MAPK signaling dynamics. Our analysis reveals that members of the SPRED family have unique protein binding partners and describes the molecular and functional determinants of SPRED2-RSK2 complex dynamics. more...
- Published
- 2023
7. Combined HRAS and NRAS ablation induces a RASopathy phenotype in mice
- Author
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Rocío Fuentes-Mateos, Rósula García-Navas, Cristina Fernández-Infante, Luis Hernández-Cano, Nuria Calzada-Nieto, Andrea Olarte-San Juan, Carmen Guerrero, Eugenio Santos, and Alberto Fernández-Medarde
- Subjects
RASopathy ,RAS isoforms ,HRAS ,NRAS ablation ,Developmental disorders ,Thrombocytopenia ,Medicine ,Cytology ,QH573-671 - Abstract
Abstract Background HRASKO/NRASKO double knockout mice exhibit exceedingly high rates of perinatal lethality due to respiratory failure caused by a significant lung maturation delay. The few animals that reach adulthood have a normal lifespan, but present areas of atelectasis mixed with patches of emphysema and normal tissue in the lung. Methods Eight double knockout and eight control mice were analyzed using micro-X-ray computerized tomography and a Small Animal Physiological Monitoring system. Tissues and samples from these mice were analyzed using standard histological and Molecular Biology methods and the significance of the results analyzed using a Student´s T-test. Results The very few double knockout mice surviving up to adulthood display clear craniofacial abnormalities reminiscent of those seen in RASopathy mouse models, as well as thrombocytopenia, bleeding anomalies, and reduced platelet activation induced by thrombin. These surviving mice also present heart and spleen hyperplasia, and elevated numbers of myeloid-derived suppressor cells in the spleen. Mechanistically, we observed that these phenotypic alterations are accompanied by increased KRAS-GTP levels in heart, platelets and primary mouse embryonic fibroblasts from these animals. Conclusions Our data uncovers a new, previously unidentified mechanism capable of triggering a RASopathy phenotype in mice as a result of the combined removal of HRAS and NRAS. more...
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- 2024
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8. A case of systemic lupus erythematosus in a patient with Noonan syndrome with recurrent severe hypoglycaemia.
- Author
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Shotaro Masuoka, Takashi Tanaka, Miwa Kanaji, Karin Furukawa, Keiko Koshiba, Zento Yamada, Eri Watanabe, Mai Kawazoe, Shun Ito, Ayako Fuchigami, and Toshihiro Nanki
- Subjects
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AUTOIMMUNE thyroiditis , *SOMATOMEDIN C , *METABOLIC syndrome , *B cell receptors , *AUTOIMMUNE hepatitis , *ANTIPHOSPHOLIPID syndrome - Abstract
This article presents a case study of a patient with Noonan syndrome (NS) who developed systemic lupus erythematosus (SLE) and experienced recurrent severe hypoglycemia. NS is a genetic disorder that can lead to the development of autoimmune diseases, including SLE. The patient in this case exhibited various symptoms of SLE and was successfully treated with glucocorticoids. The article suggests a potential association between NS and autoimmune diseases, but further research is needed to understand the underlying mechanisms. [Extracted from the article] more...
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- 2024
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9. Combined HRAS and NRAS ablation induces a RASopathy phenotype in mice.
- Author
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Fuentes-Mateos, Rocío, García-Navas, Rósula, Fernández-Infante, Cristina, Hernández-Cano, Luis, Calzada-Nieto, Nuria, Juan, Andrea Olarte-San, Guerrero, Carmen, Santos, Eugenio, and Fernández-Medarde, Alberto more...
- Subjects
THROMBIN receptors ,LUNGS ,MYELOID-derived suppressor cells ,HEART ,ETIOLOGY of diseases ,MOLECULAR biology ,PHENOTYPES ,COMPUTED tomography - Abstract
Background: HRAS
KO /NRASKO double knockout mice exhibit exceedingly high rates of perinatal lethality due to respiratory failure caused by a significant lung maturation delay. The few animals that reach adulthood have a normal lifespan, but present areas of atelectasis mixed with patches of emphysema and normal tissue in the lung. Methods: Eight double knockout and eight control mice were analyzed using micro-X-ray computerized tomography and a Small Animal Physiological Monitoring system. Tissues and samples from these mice were analyzed using standard histological and Molecular Biology methods and the significance of the results analyzed using a Student´s T-test. Results: The very few double knockout mice surviving up to adulthood display clear craniofacial abnormalities reminiscent of those seen in RASopathy mouse models, as well as thrombocytopenia, bleeding anomalies, and reduced platelet activation induced by thrombin. These surviving mice also present heart and spleen hyperplasia, and elevated numbers of myeloid-derived suppressor cells in the spleen. Mechanistically, we observed that these phenotypic alterations are accompanied by increased KRAS-GTP levels in heart, platelets and primary mouse embryonic fibroblasts from these animals. Conclusions: Our data uncovers a new, previously unidentified mechanism capable of triggering a RASopathy phenotype in mice as a result of the combined removal of HRAS and NRAS. [ABSTRACT FROM AUTHOR] more...- Published
- 2024
- Full Text
- View/download PDF
10. Multiple central giant cell granuloma of the jaws: diagnostic signposts of Noonan syndrome and RASopathy.
- Author
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Friedrich, Reinhard E., Rutkowski, Rico, and Gosau, Martin
- Subjects
NOONAN syndrome ,GRANULOMA ,JAWS ,SURGICAL diagnosis ,FACIAL injuries - Abstract
Noonan syndrome (NS) is a phenotypically variable inherited multi-system disorder. Maxillofacial findings can be diagnostic, especially in the evaluation of discrete facial dysmorphia. Diagnostic landmark findings of therapeutic relevance for the jaws such as central giant cell granuloma (CGCG) are rare in NS. However, recent molecular genetic studies indicate that these rare, benign lesions are neoplasms and more common in specific syndromes grouped under the umbrella term RASopathies. A specialist surgical diagnosis can be helpful in identifying the underlying disease. This report outlines diagnosis and treatment of a case of CGCG for which jaw diagnosis became the key to identifying a syndromic disease. [ABSTRACT FROM AUTHOR] more...
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- 2024
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11. SYNGAP1: The Gene and Syndrome
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Witzig, Derek, Patel, Het, Hong, Ingie, Gupta, Siddarth, Huganir, Richard, Smith-Hicks, Constance, and Rauen, Katherine A., editor
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- 2024
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12. Cardio-Facio-Cutaneous Syndrome
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Rauen, Katherine A., Tidyman, William E., and Rauen, Katherine A., editor
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- 2024
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13. Noonan Syndrome with Multiple Lentigines
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Hodgson, Myles C., Chennappan, Saravanakkumar, Kontaridis, Maria Irene, and Rauen, Katherine A., editor
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- 2024
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14. Clinical Studies and Small Molecule Inhibitors for RASopathy Treatment
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Gross, Andrea M., Yohe, Marielle E., Widemann, Brigitte C., and Rauen, Katherine A., editor
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- 2024
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15. Noonan Syndrome
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Roberts, Amy E. and Rauen, Katherine A., editor
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- 2024
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16. Skeletal Muscle Development in the RASopathies
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Tidyman, William E. and Rauen, Katherine A., editor
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- 2024
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17. Behavioral Profile in RASopathies
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Axelrad, Marni E., Katzenstein, Jennifer, Schwartz, David D., and Rauen, Katherine A., editor
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- 2024
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18. Mosaic RASopathies
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Meyer, Summer N., Love, Nick R., Kiuru, Maija, and Rauen, Katherine A., editor
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- 2024
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19. The RAS-Regulated RAF-MEK1/2-ERK1/2 Protein Kinase Pathway: The Path Most Traveled in RASopathies
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Dutkiewicz, Roksana A., Sharpe, Hayley J., Cook, Simon J., and Rauen, Katherine A., editor
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- 2024
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20. Understanding the RAS in RASopathies
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McCormick, Frank and Rauen, Katherine A., editor
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- 2024
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21. What Is a RASopathy?
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Rauen, Katherine A. and Rauen, Katherine A., editor
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- 2024
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22. Prenatal Manifestations of the RASopathies
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Meiss, Lauren N., Sparks, Teresa N., Jelin, Angie C., and Rauen, Katherine A., editor
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- 2024
- Full Text
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23. The Importance of Advocacy in the RASopathies
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Schoyer, Lisa, Stronach, Beth, and Rauen, Katherine A., editor
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- 2024
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24. Central Conducting Lymphatic Anomalies
- Author
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Qu, Hui-Qi, Li, Dong, Hakonarson, Hakon, and Rauen, Katherine A., editor
- Published
- 2024
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25. Case report: MEK inhibitor as treatment for multi-lineage mosaic KRAS G12D-associated epidermal nevus syndrome in a pediatric patient
- Author
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Margarita Dionysiou, Stavriani C. Makri, Shivani Ahlawat, Melike Guryildirim, Kristin W. Barañano, Mari L. Groves, Pedram Argani, and Christine A. Pratilas
- Subjects
RASopathy ,KRAS G12D ,hypertrophic neuropathy ,selumetinib ,epidermal nevus syndrome ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
The RASopathies, collectively, are a spectrum of genetic syndromes caused by mutations in genes involved in the RAS/ mitogen-activated protein kinase (MAPK) pathway, including but not limited to PTPN11, NRAS, KRAS, HRAS, BRAF, and MAP2K1. Recognized RASopathy conditions include neurofibromatosis type 1 (NF1), Noonan syndrome, capillary malformation-arteriovenous malformation syndrome, Costello syndrome, cardiofacio-cutaneous (CFC) syndrome, LEOPARD syndrome and Legius syndrome. The RASopathies often display overlapping clinical features, presumably owing to common RAS-MAPK signaling pathway activation driving dysregulated cell proliferation. Epidermal nevus syndromes (ENS) are described as the presence of epidermal nevi, in individuals also affected by extra-cutaneous organ system involvement, and there is recent recognition of mosaic RAS mutations as molecular drivers of ENS. Currently, no curative treatments exist for RASopathy driven conditions, but rather symptom-directed management is the currently accepted standard. Here, we detail a unique case of a child exhibiting diffuse spinal nerve root hypertrophy in the context of epidermal nevus syndrome driven by molecularly confirmed KRAS G12D mosaicism, treated with the MEK 1/2 inhibitor selumetinib. Herein, we report the response of this patient to targeted therapy of more than two years’ duration, including stabilization of multilevel nerve root hypertrophy as well as significant improvement in epidermal nevi. While the effectiveness of MEK inhibitors such as selumetinib is established in NF1-associated inoperable plexiform neurofibromas, their use in managing hyperactive KRAS-driven epidermal nevi and hypertrophic neuropathy remains unproven, and this case, to our knowledge, is the first such case to be reported. Shared molecular dysregulation and overlapping clinical features between these conditions suggest potential for effective therapeutic application of MEK directed therapy to address a range of conditions resulting from germline and/ or mosaic expression of aberrantly regulated RAS signaling. more...
- Published
- 2024
- Full Text
- View/download PDF
26. Obstetrical and neonatal outcomes of cardio-facio-cutaneous syndrome: Prenatal consequences of Ras/MAPK dysregulation.
- Author
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Jelin, Angie, Mahle, Amanda, Tran, Susan, Sparks, Teresa, and Rauen, Katherine
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RASopathy ,Ras/MAPK ,cardio-facio-cutaneous syndrome ,prenatal ,signal transduction pathway ,Humans ,Pregnancy ,Female ,Retrospective Studies ,Fetal Macrosomia ,Polyhydramnios ,Proto-Oncogene Proteins B-raf ,Ectodermal Dysplasia ,Facies ,Heart Defects ,Congenital ,Megalencephaly - Abstract
We systematically delineated the prenatal phenotype, and obstetrical and neonatal outcomes of the RASopathy cardio-facio-cutaneous (CFC) syndrome. A comprehensive, retrospective medical history survey was distributed to parents of children with confirmed CFC in collaboration with CFC International, Inc. Data were collected on CFC gene variant, maternal characteristics, pregnancy course, delivery, and neonatal outcomes with the support of medical records. We identified 43 individuals with pathogenic variants in BRAF (81%), MEK1 (14%), or MEK2 (5%) genes. The median age was 8.5 years. Hyperemesis gravidarum, gestational diabetes, gestational hypertension, and preeclampsia occurred in 5/43 (12%), 4/43 (9%), 3/43 (7%), and 3/43 (7%) of pregnancies, respectively. Second and third trimester ultrasound abnormalities included polyhydramnios, macrocephaly, macrosomia, and renal and cardiac abnormalities. Delivery occurred via spontaneous vaginal, operative vaginal, or cesarean delivery in 15/42 (36%), 7/42 (16%), and 20/42 (48%), respectively. Median gestational age at delivery was 37 weeks and median birth weight was 3501 grams. Germline pathogenic vaiants had mutiple congenital consequences including polyhydramnios, renal and cardiac abnormalities, macrosomia, and macrocephaly on second and third trimester ultrasound. Elevated rates of operative delivery and neonatal complications were also noted. Understanding and defining a prenatal phenotype may improve prenatal prognostic counseling and outcomes. more...
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- 2023
27. Coronary arteriopathy in a patient with Noonan phenotype: Case report
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Simran Jain, M. S. Ravindra, Yogesh Chintaman Sathe, Snehal M. Kulkarni, and Ashish Banpurkar
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coronary arteriopathy ,noonan phenotype ,noonan syndrome ,rasopathy ,Medicine ,Pediatrics ,RJ1-570 ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
Noonan syndrome (NS) is a pleomorphic genetic disorder. Up to 50-80% of individuals have associated congenital heart disease. The scope of cardiac disease in NS is quite variable depending on the gene mutation. The most common forms of cardiac defects include pulmonary stenosis, hypertrophic cardiomyopathy (HCM), atrial septal defect and left-sided lesions. Amongst the rare vascular abnormalities few case reports have been mentioned about coronary artery lesions apart from sinus of Valsalva aneurysm, aortic dissection, intracranial aneurysm. This is a case report a rare case of asymptomatic coronary artery aneurysm in a young male with NS. There is lack of unified protocol for the screening, diagnosis, treatment, and follow-up of coronary artery disease in patients with NS. We conclude, echocardiography is sufficient in most cases in children. But a CT scan is appropriate in adults or when other lesions are suspected. more...
- Published
- 2024
- Full Text
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28. Natural history and outcomes in paediatric RASopathy‐associated hypertrophic cardiomyopathy
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Olga Boleti, Gabrielle Norrish, Ella Field, Kathleen Dady, Kim Summers, Gauri Nepali, Vinay Bhole, Orhan Uzun, Amos Wong, Piers E. F. Daubeney, Graham Stuart, Precylia Fernandes, Karen McLeod, Maria Ilina, Muhammad Najih Liaqath Ali, Tara Bharucha, Grazia Delle Donne, Elspeth Brown, Katie Linter, Caroline B. Jones, Jonathan Searle, William Regan, Sujeev Mathur, Nicola Boyd, Zdenka Reinhardt, Sophie Duignan, Terence Prendiville, Satish Adwani, and Juan Pablo Kaski more...
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Hypertrophic cardiomyopathy ,Paediatric cardiology ,Inherited cardiac conditions ,Genetics ,RASopathy ,Noonan ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
Abstract Aims This study aimed to describe the natural history and predictors of all‐cause mortality and sudden cardiac death (SCD)/equivalent events in children with a RASopathy syndrome and hypertrophic cardiomyopathy (HCM). Methods and results This is a retrospective cohort study from 14 paediatric cardiology centres in the United Kingdom and Ireland. We included children more...
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- 2024
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29. Structural rearrangements as a recurrent pathogenic mechanism for SETBP1 haploinsufficiency
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V. Alesi, S. Genovese, M. C. Roberti, E. Sallicandro, S. Di Tommaso, S. Loddo, V. Orlando, D. Pompili, C. Calacci, V. Mei, E. Pisaneschi, M. V. Faggiano, A. Morgia, C. Mammì, G. Astrea, R. Battini, M. Priolo, M. L. Dentici, R. Milone, and A. Novelli more...
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SETBP1 ,Optical genome mapping ,OGM ,Complex rearrangement ,Translocation ,RASopathy ,Medicine ,Genetics ,QH426-470 - Abstract
Abstract Chromosomal structural rearrangements consist of anomalies in genomic architecture that may or may not be associated with genetic material gain and loss. Evaluating the precise breakpoint is crucial from a diagnostic point of view, highlighting possible gene disruption and addressing to appropriate genotype–phenotype association. Structural rearrangements can either occur randomly within the genome or present with a recurrence, mainly due to peculiar genomic features of the surrounding regions. We report about three non-related individuals, harboring chromosomal structural rearrangements interrupting SETBP1, leading to gene haploinsufficiency. Two out of them resulted negative to Chromosomal Microarray Analysis (CMA), being the rearrangement balanced at a microarray resolution. The third one, presenting with a complex three-chromosome rearrangement, had been previously diagnosed with SETBP1 haploinsufficiency due to a partial gene deletion at one of the chromosomal breakpoints. We thoroughly characterized the rearrangements by means of Optical Genome Mapping (OGM) and Whole Genome Sequencing (WGS), providing details about the involved sequences and the underlying mechanisms. We propose structural variants as a recurrent event in SETBP1 haploinsufficiency, which may be overlooked by laboratory routine genomic analyses (CMA and Whole Exome Sequencing) or only partially determined when associated with genomic losses at breakpoints. We finally introduce a possible role of SETBP1 in a Noonan-like phenotype. more...
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- 2024
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30. MEK inhibitors for neurofibromatosis type 1 manifestations: Clinical evidence and consensus.
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de Blank, Peter MK, Gross, Andrea M, Akshintala, Srivandana, Blakeley, Jaishri O, Bollag, Gideon, Cannon, Ashley, Dombi, Eva, Fangusaro, Jason, Gelb, Bruce D, Hargrave, Darren, Kim, AeRang, Klesse, Laura J, Loh, Mignon, Martin, Staci, Moertel, Christopher, Packer, Roger, Payne, Jonathan M, Rauen, Katherine A, Rios, Jonathan J, Robison, Nathan, Schorry, Elizabeth K, Shannon, Kevin, Stevenson, David A, Stieglitz, Elliot, Ullrich, Nicole J, Walsh, Karin S, Weiss, Brian D, Wolters, Pamela L, Yohay, Kaleb, Yohe, Marielle E, Widemann, Brigitte C, and Fisher, Michael J more...
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Neurosciences ,Neurofibromatosis ,Rare Diseases ,Cancer ,Pediatric ,Child ,Humans ,Consensus ,Mitogen-Activated Protein Kinase Kinases ,Neurofibroma ,Plexiform ,Neurofibromatosis 1 ,Protein Kinase Inhibitors ,low-grade glioma ,MEK inhibitors ,neurofibromatosis type 1 ,plexiform neurofibromas ,RASopathy ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
The wide variety of clinical manifestations of the genetic syndrome neurofibromatosis type 1 (NF1) are driven by overactivation of the RAS pathway. Mitogen-activated protein kinase kinase inhibitors (MEKi) block downstream targets of RAS. The recent regulatory approvals of the MEKi selumetinib for inoperable symptomatic plexiform neurofibromas in children with NF1 have made it the first medical therapy approved for this indication in the United States, the European Union, and elsewhere. Several recently published and ongoing clinical trials have demonstrated that MEKi may have potential benefits for a variety of other NF1 manifestations, and there is broad interest in the field regarding the appropriate clinical use of these agents. In this review, we present the current evidence regarding the use of existing MEKi for a variety of NF1-related manifestations, including tumor (neurofibromas, malignant peripheral nerve sheath tumors, low-grade glioma, and juvenile myelomonocytic leukemia) and non-tumor (bone, pain, and neurocognitive) manifestations. We discuss the potential utility of MEKi in related genetic conditions characterized by overactivation of the RAS pathway (RASopathies). In addition, we review practical treatment considerations for the use of MEKi as well as provide consensus recommendations regarding their clinical use from a panel of experts. more...
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- 2022
31. Genetically confirmed coexistence of neurofibromatosis type 1 and Cherubism in a pediatric patient
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Sarantou, Sofia, Marinakis, Nikolaos M., Traeger-Synodinos, Joanne, Siomou, Ekaterini, Ntinopoulos, Argyrios, and Serbis, Anastasios
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- 2024
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32. Natural history and outcomes in paediatric RASopathy‐associated hypertrophic cardiomyopathy.
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Boleti, Olga, Norrish, Gabrielle, Field, Ella, Dady, Kathleen, Summers, Kim, Nepali, Gauri, Bhole, Vinay, Uzun, Orhan, Wong, Amos, Daubeney, Piers E. F., Stuart, Graham, Fernandes, Precylia, McLeod, Karen, Ilina, Maria, Ali, Muhammad Najih Liaqath, Bharucha, Tara, Donne, Grazia Delle, Brown, Elspeth, Linter, Katie, and Jones, Caroline B. more...
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HYPERTROPHIC cardiomyopathy ,NATURAL history ,CARDIAC arrest ,NOONAN syndrome ,VENTRICULAR tachycardia - Abstract
Aims: This study aimed to describe the natural history and predictors of all‐cause mortality and sudden cardiac death (SCD)/equivalent events in children with a RASopathy syndrome and hypertrophic cardiomyopathy (HCM). Methods and results: This is a retrospective cohort study from 14 paediatric cardiology centres in the United Kingdom and Ireland. We included children <18 years with HCM and a clinical and/or genetic diagnosis of a RASopathy syndrome [Noonan syndrome (NS), NS with multiple lentigines (NSML), Costello syndrome (CS), cardiofaciocutaneous syndrome (CFCS), and NS with loose anagen hair (NS‐LAH)]. One hundred forty‐nine patients were recruited [111 (74.5%) NS, 12 (8.05%) NSML, 6 (4.03%) CS, 6 (4.03%) CFCS, 11 (7.4%) Noonan‐like syndrome, and 3 (2%) NS‐LAH]. NSML patients had higher left ventricular outflow tract (LVOT) gradient values [60 (36–80) mmHg, P = 0.004]. Over a median follow‐up of 197.5 [inter‐quartile range (IQR) 93.58–370] months, 23 patients (15.43%) died at a median age of 24.1 (IQR 5.6–175.9) months. Survival was 96.45% [95% confidence interval (CI) 91.69–98.51], 90.42% (95% CI 84.04–94.33), and 84.12% (95% CI 75.42–89.94) at 1, 5, and 10 years, respectively, but this varied by RASopathy syndrome. RASopathy syndrome, symptoms at baseline, congestive cardiac failure (CCF), non‐sustained ventricular tachycardia (NSVT), and maximal left ventricular wall thickness were identified as predictors of all‐cause mortality on univariate analysis, and CCF, NSVT, and LVOT gradient were predictors for SCD or equivalent event. Conclusions: These findings highlight a distinct category of patients with Noonan‐like syndrome with a milder HCM phenotype but significantly worse survival and identify potential predictors of adverse outcome in patients with RASopathy‐related HCM. [ABSTRACT FROM AUTHOR] more...
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- 2024
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33. Structural rearrangements as a recurrent pathogenic mechanism for SETBP1 haploinsufficiency.
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Alesi, V., Genovese, S., Roberti, M. C., Sallicandro, E., Di Tommaso, S., Loddo, S., Orlando, V., Pompili, D., Calacci, C., Mei, V., Pisaneschi, E., Faggiano, M. V., Morgia, A., Mammì, C., Astrea, G., Battini, R., Priolo, M., Dentici, M. L., Milone, R., and Novelli, A. more...
- Abstract
Chromosomal structural rearrangements consist of anomalies in genomic architecture that may or may not be associated with genetic material gain and loss. Evaluating the precise breakpoint is crucial from a diagnostic point of view, highlighting possible gene disruption and addressing to appropriate genotype–phenotype association. Structural rearrangements can either occur randomly within the genome or present with a recurrence, mainly due to peculiar genomic features of the surrounding regions. We report about three non-related individuals, harboring chromosomal structural rearrangements interrupting SETBP1, leading to gene haploinsufficiency. Two out of them resulted negative to Chromosomal Microarray Analysis (CMA), being the rearrangement balanced at a microarray resolution. The third one, presenting with a complex three-chromosome rearrangement, had been previously diagnosed with SETBP1 haploinsufficiency due to a partial gene deletion at one of the chromosomal breakpoints. We thoroughly characterized the rearrangements by means of Optical Genome Mapping (OGM) and Whole Genome Sequencing (WGS), providing details about the involved sequences and the underlying mechanisms. We propose structural variants as a recurrent event in SETBP1 haploinsufficiency, which may be overlooked by laboratory routine genomic analyses (CMA and Whole Exome Sequencing) or only partially determined when associated with genomic losses at breakpoints. We finally introduce a possible role of SETBP1 in a Noonan-like phenotype. [ABSTRACT FROM AUTHOR] more...
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- 2024
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34. RAS isoform specific activities are disrupted by disease associated mutations during cell differentiation
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Rohan Chippalkatti, Bianca Parisi, Farah Kouzi, Christina Laurini, Nesrine Ben Fredj, and Daniel Kwaku Abankwa
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Ras ,Cancer ,RASopathy ,Flow cytometry ,Inhibitors ,Differentiation ,Cytology ,QH573-671 - Abstract
The RAS-MAPK-pathway is aberrantly regulated in cancer and developmental diseases called RASopathies. While typically the impact of Ras on the proliferation of various cancer cell lines is assessed, it is poorly established how Ras affects cellular differentiation. Here we implement the C2C12 myoblast cell line to systematically study the effect of Ras mutants and Ras-pathway drugs on differentiation. We first provide evidence that a minor pool of Pax7+ progenitors replenishes a major pool of transit amplifying cells that are ready to differentiate. Our data indicate that Ras isoforms have distinct roles in the differentiating culture, where K-Ras depletion increases and H-Ras depletion decreases terminal differentiation. This assay could therefore provide significant new insights into Ras biology and Ras-driven diseases. In line with this, we found that all oncogenic Ras mutants block terminal differentiation of transit amplifying cells. By contrast, RASopathy associated K-Ras variants were less able to block differentiation. Profiling of eight targeted Ras-pathway drugs on seven oncogenic Ras mutants revealed their allele-specific activities and distinct abilities to restore normal differentiation as compared to triggering cell death. In particular, the MEK-inhibitor trametinib could broadly restore differentiation, while the mTOR-inhibitor rapamycin broadly suppressed differentiation. We expect that this quantitative assessment of the impact of Ras-pathway mutants and drugs on cellular differentiation has great potential to complement cancer cell proliferation data. more...
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- 2024
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35. Hyperactivation of MEK1 in cortical glutamatergic neurons results in projection axon deficits and aberrant motor learning
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George R. Bjorklund, Katherina P. Rees, Kavya Balasubramanian, Lauren T. Hewitt, Kenji Nishimura, and Jason M. Newbern
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connectivity ,cortex ,development ,rasopathy ,kinase ,axon ,Medicine ,Pathology ,RB1-214 - Published
- 2024
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36. RASopathies – what they reveal about RAS/MAPK signaling in skeletal muscle development
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Katherine A. Rauen and William E. Tidyman
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cardio-facio-cutaneous syndrome ,costello syndrome ,myopathy ,neurofibromatosis type 1 ,rare disorder ,rasopathy ,ras pathway ,skeletal myogenesis ,treatment ,Medicine ,Pathology ,RB1-214 - Published
- 2024
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37. The seventh international RASopathies symposium: Pathways to a cure—expanding knowledge, enhancing research, and therapeutic discovery
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Kontaridis, Maria I, Roberts, Amy E, Schill, Lisa, Schoyer, Lisa, Stronach, Beth, Andelfinger, Gregor, Aoki, Yoko, Axelrad, Marni E, Bakker, Annette, Bennett, Anton M, Broniscer, Alberto, Castel, Pau, Chang, Caitlin A, Cyganek, Lukas, Das, Tirtha K, Hertog, Jeroen, Galperin, Emilia, Garg, Shruti, Gelb, Bruce D, Gordon, Kristiana, Green, Tamar, Gripp, Karen W, Itkin, Maxim, Kiuru, Maija, Korf, Bruce R, Livingstone, Jeff R, López‐Juárez, Alejandro, Magoulas, Pilar L, Mansour, Sahar, Milner, Theresa, Parker, Elisabeth, Pierpont, Elizabeth I, Plouffe, Kevin, Rauen, Katherine A, Shankar, Suma P, Smith, Shane B, Stevenson, David A, Tartaglia, Marco, Van, Richard, Wagner, Morgan E, Ware, Stephanie M, and Zenker, Martin more...
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Pediatric ,Genetics ,Aetiology ,2.1 Biological and endogenous factors ,Good Health and Well Being ,Costello Syndrome ,Humans ,Mitogen-Activated Protein Kinases ,Noonan Syndrome ,Signal Transduction ,ras Proteins ,cardiofaciocutaneus syndrome ,Costello syndrome ,neurofibromatosis ,Noonan syndrome ,RASopathy ,signaling ,Clinical Sciences - Abstract
RASopathies are a group of genetic disorders that are caused by genes that affect the canonical Ras/mitogen-activated protein kinase (MAPK) signaling pathway. Despite tremendous progress in understanding the molecular consequences of these genetic anomalies, little movement has been made in translating these findings to the clinic. This year, the seventh International RASopathies Symposium focused on expanding the research knowledge that we have gained over the years to enhance new discoveries in the field, ones that we hope can lead to effective therapeutic treatments. Indeed, for the first time, research efforts are finally being translated to the clinic, with compassionate use of Ras/MAPK pathway inhibitors for the treatment of RASopathies. This biannual meeting, organized by the RASopathies Network, brought together basic scientists, clinicians, clinician scientists, patients, advocates, and their families, as well as representatives from pharmaceutical companies and the National Institutes of Health. A history of RASopathy gene discovery, identification of new disease genes, and the latest research, both at the bench and in the clinic, were discussed. more...
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- 2022
38. Long-term outcomes of surgery for obstructive hypertrophic cardiomyopathy in a pediatric cohortCentral MessagePerspective
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Stephanie N. Nguyen, MD, Megan M. Chung, BA, Alice V. Vinogradsky, BA, Marc E. Richmond, MD, MS, Warren A. Zuckerman, MD, Andrew B. Goldstone, MD, PhD, and Emile A. Bacha, MD
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hypertrophic cardiomyopathy ,RASopathy ,Noonan syndrome ,transaortic septal myectomy ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 ,Surgery ,RD1-811 - Abstract
Background: Septal reduction therapy via septal myectomy or a modified Konno procedure is the mainstay of therapy for drug-refractory obstructive hypertrophic cardiomyopathy (HCM), although outcomes data on septal myectomy in pediatric patients are limited. We evaluated long-term outcomes following surgery for obstructive HCM in a pediatric cohort. Methods: We retrospectively reviewed patients age ≤18 years with obstructive HCM who underwent a left and/or right ventricular septal myectomy at our institution between 1992 and 2022. Primary endpoints were transplantation-free survival, freedom from HCM-related death, and cumulative probability of HCM-related reintervention. We further evaluated outcomes in patients with and without Noonan syndrome or other RASopathies. Results: Thirty-seven patients (median age, 7.4 years; interquartile range [IQR], 3.4-12.9 years) underwent transaortic septal myectomy. A combined modified Konno procedure was performed in 5 patients (13.9%). Sixteen patients (43.2%) had a RASopathy. A concomitant right ventricular outflow tract resection was performed in 9 patients (24.3%). There was 1 (2.7%) in-hospital death and 4 late deaths at a median follow-up of 10.5 years (IQR, 0.1-29.3). Twenty-year transplant-free survival and freedom from HCM-related death were 80.6% (95% confidence interval [CI], 64.2%-100%) and 87.1% (95% CI, 71.8%-100%), respectively. The 20-year cumulative probability of HCM-related reintervention was 34.2% (95% CI, 12.8%-57.1%). Seven patients required a septal reintervention. There was no difference in any primary endpoints between patients with and without a RASopathy. Conclusions: Surgery for obstructive HCM, including septal myectomy with and without a modified Konno procedure, may be performed with low morbidity and good long-term outcomes in pediatric patients. Recurrent outflow tract obstruction is not uncommon. more...
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- 2023
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39. Cross-species analysis of LZTR1 loss-of-function mutants demonstrates dependency to RIT1 orthologs.
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Cuevas-Navarro, Antonio, Rodriguez-Muñoz, Laura, Grego-Bessa, Joaquim, Cheng, Alice, Rauen, Katherine A, Urisman, Anatoly, McCormick, Frank, Jimenez, Gerardo, and Castel, Pau
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Animals ,Mice ,ras Proteins ,Adaptor Proteins ,Signal Transducing ,Drosophila Proteins ,Transcription Factors ,Signal Transduction ,Cell Proliferation ,Ubiquitination ,CG3711 ,D. melanogaster ,LZTR1 ,RASopathy ,RIC ,RIT1 ,cancer biology ,genetics ,genomics ,human ,mouse ,noonan syndrome ,1.1 Normal biological development and functioning ,Underpinning research ,Generic health relevance ,D ,melanogaster ,Human ,Mouse ,Biochemistry and Cell Biology - Abstract
RAS GTPases are highly conserved proteins involved in the regulation of mitogenic signaling. We have previously described a novel Cullin 3 RING E3 ubiquitin ligase complex formed by the substrate adaptor protein LZTR1 that binds, ubiquitinates, and promotes proteasomal degradation of the RAS GTPase RIT1. In addition, others have described that this complex is also responsible for the ubiquitination of classical RAS GTPases. Here, we have analyzed the phenotypes of Lztr1 loss-of-function mutants in both fruit flies and mice and have demonstrated a biochemical preference for their RIT1 orthologs. Moreover, we show that Lztr1 is haplosufficient in mice and that embryonic lethality of the homozygous null allele can be rescued by deletion of Rit1. Overall, our results indicate that, in model organisms, RIT1 orthologs are the preferred substrates of LZTR1. more...
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- 2022
40. Exome sequencing vs targeted gene panels for the evaluation of nonimmune hydrops fetalis
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Norton, Mary E, Ziffle, Jessica Van, Lianoglou, Billie R, Hodoglugil, Ugur, Devine, W Patrick, and Sparks, Teresa N
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Reproductive Medicine ,Biomedical and Clinical Sciences ,Clinical Research ,Human Genome ,Rare Diseases ,Genetics ,Biotechnology ,Pediatric ,Genetic Testing ,Good Health and Well Being ,Adult ,Cohort Studies ,Female ,Gestational Age ,High-Throughput Nucleotide Sequencing ,Humans ,Hydrops Fetalis ,Predictive Value of Tests ,Pregnancy ,Prenatal Diagnosis ,Exome Sequencing ,exome sequencing ,nonimmune hydrops ,RASopathy ,targeted gene panels ,Paediatrics and Reproductive Medicine ,Obstetrics & Reproductive Medicine ,Reproductive medicine - Abstract
BackgroundNext-generation sequencing is increasingly used in prenatal diagnosis. Targeted gene panels and exome sequencing are both available, but the comparative diagnostic yields of these approaches are not known.ObjectiveWe compared the diagnostic yield of exome sequencing with the simulated application of commercial targeted gene panels in a large cohort of fetuses with nonimmune hydrops fetalis.Study designThis was a secondary analysis of a cohort study of exome sequencing for nonimmune hydrops fetalis, in which recruitment, exome sequencing, and phenotype-driven variant analysis were completed in 127 pregnancies with features of nonimmune hydrops fetalis. An Internet search was performed to identify commercial laboratories that offer targeted gene panels for the prenatal evaluation of nonimmune hydrops fetalis or for specific disorders associated with nonimmune hydrops fetalis using the terms "non-immune hydrops fetalis," "fetal non-immune hydrops," "hydrops," "cystic hygroma," "lysosomal storage disease," "metabolic disorder," "inborn error of metabolism," "RASopathy," and "Noonan." Our primary outcome was the proportion of all genetic variants identified through exome sequencing that would have been identified if a targeted gene panel had instead been used. The secondary outcomes were the proportion of genetic variants that would have been identified by type of targeted gene panel (general nonimmune hydrops fetalis, RASopathy, or metabolic) and the percent of variants of uncertain significance that would have been identified on the panels, assuming 100% analytical sensitivity and specificity of panels for variants in the included genes.ResultsExome sequencing identified a pathogenic or likely pathogenic variant in 37 of 127 cases (29%) in a total of 29 genes. A variant of uncertain significance, strongly suspected to be associated with the phenotype, was identified in another 12 cases (9%). We identified 7 laboratories that offer 10 relevant targeted gene panels; 6 are described as RASopathy panels, 3 as nonimmune hydrops fetalis panels, and 1 as a metabolic panel. The median number of genes included on each of these panels is 22, ranging from 11 to 148. Had a nonimmune hydrops fetalis targeted gene panel been used instead of exome sequencing, 13 to 15 of the 29 genes (45%-52%) identified in our nonimmune hydrops fetalis cohort would have been sequenced, and 19 to 24 of the pathogenic variants (51%-62%) would have been detected. The yield was predicted to be the lowest with the metabolic panel (11%) and the highest with the largest nonimmune hydrops fetalis panel (62%). The largest nonimmune hydrops fetalis targeted gene panel would have had a diagnostic yield of 18% compared with 29% with exome sequencing. The exome sequencing platform used provided 30× or more coverage for all of the exons on the commercial targeted gene panels, supporting our assumption of 100% analytical sensitivity for exome sequencing.ConclusionThe broader coverage of exome sequencing for genetically heterogeneous disorders, such as nonimmune hydrops fetalis, made it a superior alternative to targeted gene panel testing. more...
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- 2022
41. Molecular and phenotypic spectrum of cardio-facio-cutaneous syndrome in Chinese patients
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Biyun Feng, Xin Li, Qianwen Zhang, Yirou Wang, Shili Gu, Ru-en Yao, Zhiying Li, Shiyang Gao, Guoying Chang, Qun Li, Niu Li, Lijun Fu, Jian Wang, and Xiumin Wang
- Subjects
Cardio-facio-cutaneous syndrome ,RASopathy ,BRAF ,MAP2K1/2 ,Medicine - Abstract
Abstract Background Cardio-facio-cutaneous (CFC) syndrome is a RASopathy subtype that presents with unique craniofacial dysmorphology, congenital heart disease, dermatologic abnormalities, growth retardation, and intellectual disability. This study describes the phenotypic spectrum of CFC in China and its association with CFC syndrome gene variants. Results Twenty Chinese CFC patients, aged 0.6–9.5 years old, were included in this study and their clinical phenotypic spectrum was compared with that of 186 patients with CFC from non-Chinese ethnicities. All 20 Chinese patients with CFC carried de novo heterozygous BRAF, MAP2K1, and MAP2K2 variants. Two novel variants were detected and consistently predicted to be deleterious using bioinformatic tools. The clinical features of CFC in the Chinese patients included hypertrophic cardiomyopathy (2/20, 10%), pulmonary valve stenosis (2/20, 10%), curly or sparse hair (7/20, 35%), epilepsy (1/20, 5%), and hypotonia (10/20, 50%); these features were less frequently observed in Chinese patients than non-Chinese patients (p more...
- Published
- 2023
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42. Prenatal and infantile diagnosis of craniosynostosis in individuals with RASopathies.
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Serbinski, Carolyn R., Vanderwal, April, Chadwell, Sarah E., Sanchez, Ana Isabel, Hopkin, Robert J., Hufnagel, Robert B., Weaver, K. Nicole, and Prada, Carlos E.
- Abstract
Fetuses with RASopathies can have a wide variety of anomalies including increased nuchal translucency, hydrops fetalis, and structural anomalies (typically cardiac and renal). There are few reports that describe prenatal‐onset craniosynostosis in association with a RASopathy diagnosis. We present clinical and molecular characteristics of five individuals with RASopathy and craniosynostosis. Two were diagnosed with craniosynostosis prenatally, 1 was diagnosed as a neonate, and 2 had evidence of craniosynostosis noted as neonates without formal diagnosis until later. Two of these individuals have Noonan syndrome (PTPN11 and KRAS variants) and three individuals have Cardiofaciocutaneous syndrome (KRAS variants). Three individuals had single suture synostosis and two had multiple suture involvement. The most common sutures involved were sagittal (n = 3), followed by coronal (n = 3), and lambdoid (n = 2) sutures. This case series confirms craniosynostosis as one of the prenatal findings in individuals with RASopathies and emphasizes the importance of considering a RASopathy diagnosis in fetuses with multiple anomalies in combination with craniosynostosis. [ABSTRACT FROM AUTHOR] more...
- Published
- 2024
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43. The RRAS2 pathogenic variant (c.67G>T; p. Gly23Cys) produces Noonan syndrome with embryonal rhabdomyosarcoma.
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Zeng, Lan, Wang, Jin, Zhu, Hui, Huang, Yu, Deng, Yi, Wei, Ping, Nie, Jing, Tang, Bei, Chen, Ai, and Zhu, Shuyao
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- *
NOONAN syndrome , *CHROMOSOME analysis , *RHABDOMYOSARCOMA , *SHORT stature , *STATURE - Abstract
Background: Noonan syndrome (NS) due to the RRAS2 gene, the pathogenic variant is an extremely rare RASopathies. Our objective was to identify the potential site of RRAS2, combined with the literature review, to find the correlation between clinical phenotype and genotype. De novo missense mutations affect different aspects of the RRAS2 function, leading to hyperactivation of the RAS‐MAPK signaling cascade. Methods: Conventional G‐banding was used to analyze the chromosome karyotype of the patient. Copy number variation sequencing (CNV‐seq) was used to detect the chromosomal gene microstructure of the patient and her parents. The exomes of the patient and her parents were sequenced using trio‐based whole exome sequencing (trio‐WES) technology. The candidate variant was verified by Sanger sequencing. The pathogenicity of the variant was predicted with a variety of bioinformatics tools. Results: Chromosome analysis of the proband revealed 46, XX, and no abnormality was found by CNV‐seq. After sequencing and bioinformatics filtering, the variant of RRAS2(c.67G>T; p. Gly23Cys) was found in the proband, while the mutation was absent in her parents. To the best of our knowledge, our patient was with the typical Noonan syndrome, such as short stature, facial dysmorphism, and developmental delay. Furthermore, our study is the first case of NS with embryonal rhabdomyosarcoma (ERMS) caused by the RRAS2 gene mutation reported in China. Conclusions: Our investigations suggested that the heterozygous missense of RRAS2 may be a potential causal variant in a rare cause of Noonan syndrome, expanding our understanding of the causally relevant mutations for this disorder. [ABSTRACT FROM AUTHOR] more...
- Published
- 2024
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44. Next generation sequencing aids diagnosis and management in a case of encephalocraniocutaneous lipomatosis.
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Barry, Kelly K., Liang, Marilyn G., Balkin, Daniel M., Srivastava, Siddharth, Church, Alanna J., and Eng, Whitney
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- *
NUCLEOTIDE sequencing , *LIPOMATOSIS , *BRAIN tumors , *GENETIC testing , *NEUROCUTANEOUS disorders , *MOLECULAR diagnosis - Abstract
Encephalocraniocutaneous lipomatosis (ECCL) is a rare neurocutaneous disorder caused by somatic FGFR1 and KRAS variants. It shares significant phenotypic overlap with several closely related disorders caused by mutations in the RAS‐MAPK pathway (mosaic RASopathies). We report a diagnostically challenging case of ECCL in which next‐generation sequencing of affected tissue identified a pathologic FGFR1 p.K656E variant, thereby establishing a molecular diagnosis. Patients with FGFR1‐associated ECCL carry a risk of developing malignant brain tumors; thus, genetic testing of patients with suspected ECCL has important management implications. [ABSTRACT FROM AUTHOR] more...
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- 2024
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45. Coronary arteriopathy in a patient with Noonan phenotype: Case report.
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Jain, Simran, Ravindra, M. S., Sathe, Yogesh Chintaman, Kulkarni, Snehal M., and Banpurkar, Ashish
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CORONARY artery abnormalities ,ANEURYSMS ,CONGENITAL heart disease ,AORTIC aneurysms ,INTRACRANIAL aneurysms ,CORONARY disease ,NOONAN syndrome ,PULMONARY stenosis ,AORTIC dissection ,COMPUTED tomography ,CARDIAC hypertrophy ,ATRIAL septal defects ,SINUS of valsalva ,GENETIC mutation ,CORONARY artery disease ,CORONARY angiography ,PHENOTYPES ,ECHOCARDIOGRAPHY ,DISEASE complications ,ADULTS - Abstract
Noonan syndrome (NS) is a pleomorphic genetic disorder. Up to 50-80% of individuals have associated congenital heart disease. The scope of cardiac disease in NS is quite variable depending on the gene mutation. The most common forms of cardiac defects include pulmonary stenosis, hypertrophic cardiomyopathy (HCM), atrial septal defect and left-sided lesions. Amongst the rare vascular abnormalities few case reports have been mentioned about coronary artery lesions apart from sinus of Valsalva aneurysm, aortic dissection, intracranial aneurysm. This is a case report a rare case of asymptomatic coronary artery aneurysm in a young male with NS. There is lack of unified protocol for the screening, diagnosis, treatment, and follow-up of coronary artery disease in patients with NS. We conclude, echocardiography is sufficient in most cases in children. But a CT scan is appropriate in adults or when other lesions are suspected. [ABSTRACT FROM AUTHOR] more...
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- 2024
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46. Structural insights into the role of SHOC2‐MRAS‐PP1C complex in RAF activation.
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Bonsor, Daniel A. and Simanshu, Dhirendra K.
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- *
RAS proteins , *MITOGEN-activated protein kinases - Abstract
RAF activation is a key step for signalling through the mitogen‐activated protein kinase (MAPK) pathway. The SHOC2 protein, along with MRAS and PP1C, forms a high affinity, heterotrimeric holoenzyme that activates RAF kinases by dephosphorylating a specific phosphoserine. Recently, our research, along with that of three other teams, has uncovered valuable structural and functional insights into the SHOC2‐MRAS‐PP1C (SMP) holoenzyme complex. In this structural snapshot, we review SMP complex assembly, the dependency on the bound‐nucleotide state of MRAS, the substitution of MRAS by the canonical RAS proteins and the roles of SHOC2 and MRAS on PP1C activity and specificity. Furthermore, we discuss the effect of several RASopathy mutations identified within the SMP complex and explore potential therapeutic approaches for targeting the SMP complex in RAS/RAF‐driven cancers and RASopathies. [ABSTRACT FROM AUTHOR] more...
- Published
- 2023
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47. Phacomatosis spilosebacea: A new name for a distinctive binary genodermatosis.
- Author
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Torchia, Daniele and Happle, Rudolf
- Abstract
Phacomatosis pigmentokeratotica (PPK) is defined by the association of papular nevus spilus arranged in a flag-like pattern and sebaceous nevus following Blaschko's lines. A systematic search of the worldwide literature retrieved 95 well-established PPK cases. An additional 30 cases were excluded for a number of reasons. Based on this study, we propose to rename PPK phacomatosis spilosebacea (PSS). Mosaic mutations of the HRAS gene are the only proven cause of PSS. The extracutaneous abnormalities of PSS result from various degrees of intermingling of Schimmelpenning syndrome and papular nevus spilus syndrome. PSS seems to be a condition at particularly high risk of developing basal cell carcinoma, urogenital malignancies, and vitamin D–resistant hypophosphatemic rickets. Extracutaneous abnormalities were detected in approximately 75% of PSS cases. [ABSTRACT FROM AUTHOR] more...
- Published
- 2023
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48. Molecular and phenotypic spectrum of cardio-facio-cutaneous syndrome in Chinese patients.
- Author
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Feng, Biyun, Li, Xin, Zhang, Qianwen, Wang, Yirou, Gu, Shili, Yao, Ru-en, Li, Zhiying, Gao, Shiyang, Chang, Guoying, Li, Qun, Li, Niu, Fu, Lijun, Wang, Jian, and Wang, Xiumin
- Subjects
CHINESE people ,MOLECULAR spectra ,HUMAN facial recognition software ,PULMONARY stenosis ,GROWTH disorders ,AGENESIS of corpus callosum ,FEEDING tubes ,IMPLANTABLE cardioverter-defibrillators - Abstract
Background: Cardio-facio-cutaneous (CFC) syndrome is a RASopathy subtype that presents with unique craniofacial dysmorphology, congenital heart disease, dermatologic abnormalities, growth retardation, and intellectual disability. This study describes the phenotypic spectrum of CFC in China and its association with CFC syndrome gene variants. Results: Twenty Chinese CFC patients, aged 0.6–9.5 years old, were included in this study and their clinical phenotypic spectrum was compared with that of 186 patients with CFC from non-Chinese ethnicities. All 20 Chinese patients with CFC carried de novo heterozygous BRAF, MAP2K1, and MAP2K2 variants. Two novel variants were detected and consistently predicted to be deleterious using bioinformatic tools. The clinical features of CFC in the Chinese patients included hypertrophic cardiomyopathy (2/20, 10%), pulmonary valve stenosis (2/20, 10%), curly or sparse hair (7/20, 35%), epilepsy (1/20, 5%), and hypotonia (10/20, 50%); these features were less frequently observed in Chinese patients than non-Chinese patients (p < 0.05). In contrast, feeding difficulties (19/20, 95%) were more frequently observed in the Chinese patients. Absent eyebrows and severe short stature were more common in patients with BRAF variants than in those with MAP2K1/2 variants. Facial recognition software was used to recognize most CFC patients using artificial intelligence. Conclusion: This study identified novel and common variants in our cohort of 20 Chinese patients with CFC. We uncovered differences in clinical features between Chinese and non-Chinese patients and detected genotype–phenotype correlations among the BRAF and MAP2K1/2 variant subgroups. This is the largest cohort of Chinese CFC patients to our knowledge, providing new insights into a subtype of RASopathy. [ABSTRACT FROM AUTHOR] more...
- Published
- 2023
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49. Structural Insights into the SPRED1-Neurofibromin-KRAS Complex and Disruption of SPRED1-Neurofibromin Interaction by Oncogenic EGFR.
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Yan, Wupeng, Markegard, Evan, Dharmaiah, Srisathiyanarayanan, Urisman, Anatoly, Drew, Matthew, Esposito, Dominic, Scheffzek, Klaus, Nissley, Dwight V, McCormick, Frank, and Simanshu, Dhirendra K
- Subjects
K562 Cells ,Humans ,Neurofibromatosis 1 ,Cafe-au-Lait Spots ,Epidermal Growth Factor ,Adaptor Proteins ,Signal Transducing ,Neurofibromin 1 ,Guanosine Triphosphate ,DNA Mutational Analysis ,Signal Transduction ,Amino Acid Sequence ,Catalytic Domain ,Protein Binding ,Phosphorylation ,Point Mutation ,Oncogenes ,Proto-Oncogene Proteins p21(ras) ,HEK293 Cells ,Protein Interaction Maps ,ErbB Receptors ,Protein Domains ,Legius syndrome ,RAS-RAF-ERK pathway ,RASopathy ,RasGAP ,neurofibromatosis type 1 ,Cancer ,Rare Diseases ,2.1 Biological and endogenous factors ,1.1 Normal biological development and functioning ,Aetiology ,Underpinning research ,Generic health relevance ,Biochemistry and Cell Biology ,Medical Physiology - Abstract
Sprouty-related, EVH1 domain-containing (SPRED) proteins negatively regulate RAS/mitogen-activated protein kinase (MAPK) signaling following growth factor stimulation. This inhibition of RAS is thought to occur primarily through SPRED1 binding and recruitment of neurofibromin, a RasGAP, to the plasma membrane. Here, we report the structure of neurofibromin (GTPase-activating protein [GAP]-related domain) complexed with SPRED1 (EVH1 domain) and KRAS. The structure provides insight into how the membrane targeting of neurofibromin by SPRED1 allows simultaneous interaction with activated KRAS. SPRED1 and NF1 loss-of-function mutations occur across multiple cancer types and developmental diseases. Analysis of the neurofibromin-SPRED1 interface provides a rationale for mutations observed in Legius syndrome and suggests why SPRED1 can bind to neurofibromin but no other RasGAPs. We show that oncogenic EGFR(L858R) signaling leads to the phosphorylation of SPRED1 on serine 105, disrupting the SPRED1-neurofibromin complex. The structural, biochemical, and biological results provide new mechanistic insights about how SPRED1 interacts with neurofibromin and regulates active KRAS levels in normal and pathologic conditions. more...
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- 2020
50. The sixth international RASopathies symposium: Precision medicine-From promise to practice.
- Author
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Gripp, Karen W, Schill, Lisa, Schoyer, Lisa, Stronach, Beth, Bennett, Anton M, Blaser, Susan, Brown, Amanda, Burdine, Rebecca, Burkitt-Wright, Emma, Castel, Pau, Darilek, Sandra, Dias, Alwyn, Dyer, Tuesdi, Ellis, Michelle, Erickson, Gregg, Gelb, Bruce D, Green, Tamar, Gross, Andrea, Ho, Alan, Holder, James Lloyd, Inoue, Shin-Ichi, Jelin, Angie C, Kennedy, Annie, Klein, Richard, Kontaridis, Maria I, Magoulas, Pilar, McConnell, Darryl B, McCormick, Frank, Neel, Benjamin G, Prada, Carlos E, Rauen, Katherine A, Roberts, Amy, Rodriguez-Viciana, Pablo, Rosen, Neal, Rumbaugh, Gavin, Sablina, Anna, Solman, Maja, Tartaglia, Marco, Thomas, Angelica, Timmer, William C, Venkatachalam, Kartik, Walsh, Karin S, Wolters, Pamela L, Yi, Jae-Sung, Zenker, Martin, and Ratner, Nancy more...
- Subjects
Humans ,Genetic Diseases ,Inborn ,ras Proteins ,Mitogen-Activated Protein Kinase Kinases ,Signal Transduction ,Germ-Line Mutation ,Costello syndrome ,Noonan syndrome ,RASopathy ,cardio-facio-cutaneous syndrome ,kinases ,neurofibromatosis ,Rare Diseases ,Genetics ,Good Health and Well Being ,Clinical Sciences - Abstract
The RASopathies are a group of genetic disorders that result from germline pathogenic variants affecting RAS-mitogen activated protein kinase (MAPK) pathway genes. RASopathies share RAS/MAPK pathway dysregulation and share phenotypic manifestations affecting numerous organ systems, causing lifelong and at times life-limiting medical complications. RASopathies may benefit from precision medicine approaches. For this reason, the Sixth International RASopathies Symposium focused on exploring precision medicine. This meeting brought together basic science researchers, clinicians, clinician scientists, patient advocates, and representatives from pharmaceutical companies and the National Institutes of Health. Novel RASopathy genes, variants, and animal models were discussed in the context of medication trials and drug development. Attempts to define and measure meaningful endpoints for treatment trials were discussed, as was drug availability to patients after trial completion. more...
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- 2020
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