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  1. Article ; Online: Defining RASopathy.

    Rauen, Katherine A

    Disease models & mechanisms

    2022  Volume 15, Issue 2

    Abstract: The term RASopathy was originally created to describe a phenotypically similar group of medical genetic syndromes caused by germline pathogenic variants in components of the RAS/mitogen-activated protein kinase (RAS/MAPK) pathway. In defining a RASopathy ...

    Abstract The term RASopathy was originally created to describe a phenotypically similar group of medical genetic syndromes caused by germline pathogenic variants in components of the RAS/mitogen-activated protein kinase (RAS/MAPK) pathway. In defining a RASopathy syndrome, one needs to consider the complex nature of the RAS/MAPK pathway, the numerous genes and regulatory components involved, its crosstalk with other signaling pathways and the phenotypic spectrum among these syndromes. Three main guiding principles to the definition should be considered. First, a RASopathy is a clinical syndrome with overlapping phenotypic features caused by germline pathogenic variants associated with the RAS/MAPK pathway. Second, a RASopathy is caused by multiple pathogenetic mechanisms, all of which lead to a similar outcome of RAS/MAPK pathway activation/dysregulation. Finally, because a RASopathy has dysfunctional germline RAS/MAPK pathway activation/dysregulation, it may, therefore, be amenable to treatment with pathway modulators.
    MeSH term(s) Genes, ras ; Humans ; Mitogen-Activated Protein Kinases/metabolism ; Signal Transduction/genetics ; Syndrome
    Chemical Substances Mitogen-Activated Protein Kinases (EC 2.7.11.24)
    Language English
    Publishing date 2022-02-01
    Publishing country England
    Document type Journal Article
    ZDB-ID 2451104-3
    ISSN 1754-8411 ; 1754-8403
    ISSN (online) 1754-8411
    ISSN 1754-8403
    DOI 10.1242/dmm.049344
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  2. Article ; Online: Defining RASopathy

    Katherine A. Rauen

    Disease Models & Mechanisms, Vol 15, Iss

    2022  Volume 2

    Abstract: The term RASopathy was originally created to describe a phenotypically similar group of medical genetic syndromes caused by germline pathogenic variants in components of the RAS/mitogen-activated protein kinase (RAS/MAPK) pathway. In defining a RASopathy ...

    Abstract The term RASopathy was originally created to describe a phenotypically similar group of medical genetic syndromes caused by germline pathogenic variants in components of the RAS/mitogen-activated protein kinase (RAS/MAPK) pathway. In defining a RASopathy syndrome, one needs to consider the complex nature of the RAS/MAPK pathway, the numerous genes and regulatory components involved, its crosstalk with other signaling pathways and the phenotypic spectrum among these syndromes. Three main guiding principles to the definition should be considered. First, a RASopathy is a clinical syndrome with overlapping phenotypic features caused by germline pathogenic variants associated with the RAS/MAPK pathway. Second, a RASopathy is caused by multiple pathogenetic mechanisms, all of which lead to a similar outcome of RAS/MAPK pathway activation/dysregulation. Finally, because a RASopathy has dysfunctional germline RAS/MAPK pathway activation/dysregulation, it may, therefore, be amenable to treatment with pathway modulators.
    Keywords Medicine ; R ; Pathology ; RB1-214
    Language English
    Publishing date 2022-02-01T00:00:00Z
    Publisher The Company of Biologists
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Melanocytic neoplasms in neurofibromatosis type 1: a systematic review.

    Meyer, Summer N / Simmons, Elanee / Studer, Amy C / Rauen, Katherine A / Kiuru, Maija

    Melanoma research

    2023  Volume 33, Issue 6, Page(s) 437–446

    Abstract: Neurofibromatosis type 1 ( NF1 ) is commonly mutated in melanoma, yet the risk of melanoma in individuals with NF1 is incompletely understood. We performed a systematic review to investigate the risk and characteristics of melanoma and melanocytic nevi ... ...

    Abstract Neurofibromatosis type 1 ( NF1 ) is commonly mutated in melanoma, yet the risk of melanoma in individuals with NF1 is incompletely understood. We performed a systematic review to investigate the risk and characteristics of melanoma and melanocytic nevi in NF1 individuals. PubMed was searched for articles describing NF1 individuals with melanoma, or melanocytic nevi. Those with cutaneous and ocular melanomas were compared to the general population using Surveillance, Epidemiology, and End Results data. Fifty-three articles describing 188 NF1 patients were included (melanoma n  = 82, melanocytic nevi n  = 93, melanocytic nevi, and melanoma n  = 13). Compared to the general population, NF1 patients with cutaneous melanomas had earlier melanoma diagnoses (49.1 vs. 58.6 years, P = 0.012), thicker tumors (3.7 vs. 1.2 mm, P = 0.006), and more frequent disease-specific deaths (27.3% vs. 8.6%, P = 0.005) with shorter survival (12.9 vs. 34.2 months, P = 0.011). Ocular melanomas made up 15.0% of all melanomas in NF1 patients versus 1.5% in the general population ( P < 0.001). In pooling all population-based studies describing melanoma in NF1 populations, NF1 individuals had 2.55 higher odds of having melanoma compared to the general population. A nevus spilus was commonly reported among NF1 individuals with nevi (44.8%, 39/87). Our findings suggest that NF1 individuals may have a higher risk for developing melanomas and tend to have thicker melanomas and worse survival compared to the general population, highlighting the importance of cutaneous and ophthalmologic surveillance in NF1 patients. Our review also supports the association between NF1 and nevus spilus.
    MeSH term(s) Humans ; Melanoma/pathology ; Skin Neoplasms/pathology ; Neurofibromatosis 1/complications ; Nevus, Pigmented/pathology ; Nevus
    Language English
    Publishing date 2023-08-14
    Publishing country England
    Document type Systematic Review ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1095779-0
    ISSN 1473-5636 ; 0960-8931
    ISSN (online) 1473-5636
    ISSN 0960-8931
    DOI 10.1097/CMR.0000000000000912
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  4. Article ; Online: The duality of human oncoproteins: drivers of cancer and congenital disorders.

    Castel, Pau / Rauen, Katherine A / McCormick, Frank

    Nature reviews. Cancer

    2020  Volume 20, Issue 7, Page(s) 383–397

    Abstract: Human oncoproteins promote transformation of cells into tumours by dysregulating the signalling pathways that are involved in cell growth, proliferation and death. Although oncoproteins were discovered many years ago and have been widely studied in the ... ...

    Abstract Human oncoproteins promote transformation of cells into tumours by dysregulating the signalling pathways that are involved in cell growth, proliferation and death. Although oncoproteins were discovered many years ago and have been widely studied in the context of cancer, the recent use of high-throughput sequencing techniques has led to the identification of cancer-associated mutations in other conditions, including many congenital disorders. These syndromes offer an opportunity to study oncoprotein signalling and its biology in the absence of additional driver or passenger mutations, as a result of their monogenic nature. Moreover, their expression in multiple tissue lineages provides insight into the biology of the proto-oncoprotein at the physiological level, in both transformed and unaffected tissues. Given the recent paradigm shift in regard to how oncoproteins promote transformation, we review the fundamentals of genetics, signalling and pathogenesis underlying oncoprotein duality.
    MeSH term(s) Animals ; Cell Transformation, Neoplastic/genetics ; Cell Transformation, Neoplastic/metabolism ; Congenital Abnormalities/genetics ; Congenital Abnormalities/metabolism ; Disease Models, Animal ; Gene-Environment Interaction ; Genetic Diseases, Inborn/genetics ; Genetic Diseases, Inborn/metabolism ; Humans ; Mice ; Mutation/genetics ; Neoplasms/genetics ; Neoplasms/metabolism ; Proto-Oncogene Proteins/genetics ; Proto-Oncogene Proteins/metabolism ; Proto-Oncogene Proteins/physiology ; Signal Transduction
    Chemical Substances Proto-Oncogene Proteins
    Language English
    Publishing date 2020-04-27
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2062767-1
    ISSN 1474-1768 ; 1474-175X
    ISSN (online) 1474-1768
    ISSN 1474-175X
    DOI 10.1038/s41568-020-0256-z
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  5. Article ; Online: Obstetrical and neonatal outcomes of cardio-facio-cutaneous syndrome: Prenatal consequences of Ras/MAPK dysregulation.

    Jelin, Angie C / Mahle, Amanda / Tran, Susan H / Sparks, Teresa N / Rauen, Katherine A

    American journal of medical genetics. Part A

    2022  Volume 191, Issue 2, Page(s) 323–331

    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 ...

    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.
    MeSH term(s) Humans ; Pregnancy ; Female ; Retrospective Studies ; Fetal Macrosomia ; Polyhydramnios ; Proto-Oncogene Proteins B-raf/genetics ; Ectodermal Dysplasia/diagnosis ; Ectodermal Dysplasia/genetics ; Ectodermal Dysplasia/pathology ; Facies ; Heart Defects, Congenital/diagnosis ; Heart Defects, Congenital/genetics ; Heart Defects, Congenital/pathology ; Megalencephaly
    Chemical Substances Proto-Oncogene Proteins B-raf (EC 2.7.11.1)
    Language English
    Publishing date 2022-10-29
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2108614-X
    ISSN 1552-4833 ; 0148-7299 ; 1552-4825
    ISSN (online) 1552-4833
    ISSN 0148-7299 ; 1552-4825
    DOI 10.1002/ajmg.a.63020
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  6. Article ; Online: The RASopathies.

    Rauen, Katherine A

    Annual review of genomics and human genetics

    2013  Volume 14, Page(s) 355–369

    Abstract: The RASopathies are a clinically defined group of medical genetic syndromes caused by germline mutations in genes that encode components or regulators of the Ras/mitogen-activated protein kinase (MAPK) pathway. These disorders include neurofibromatosis ... ...

    Abstract The RASopathies are a clinically defined group of medical genetic syndromes caused by germline mutations in genes that encode components or regulators of the Ras/mitogen-activated protein kinase (MAPK) pathway. These disorders include neurofibromatosis type 1, Noonan syndrome, Noonan syndrome with multiple lentigines, capillary malformation-arteriovenous malformation syndrome, Costello syndrome, cardio-facio-cutaneous syndrome, and Legius syndrome. Because of the common underlying Ras/MAPK pathway dysregulation, the RASopathies exhibit numerous overlapping phenotypic features. The Ras/MAPK pathway plays an essential role in regulating the cell cycle and cellular growth, differentiation, and senescence, all of which are critical to normal development. Therefore, it is not surprising that Ras/MAPK pathway dysregulation has profound deleterious effects on both embryonic and later stages of development. The Ras/MAPK pathway has been well studied in cancer and is an attractive target for small-molecule inhibition to treat various malignancies. The use of these molecules to ameliorate developmental defects in the RASopathies is under consideration.
    MeSH term(s) Animals ; Congenital Abnormalities/drug therapy ; Congenital Abnormalities/embryology ; Congenital Abnormalities/metabolism ; Congenital Abnormalities/physiopathology ; Humans ; MAP Kinase Signaling System ; Neoplasms/metabolism ; ras Proteins/metabolism
    Chemical Substances ras Proteins (EC 3.6.5.2)
    Language English
    Publishing date 2013-07-15
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Review
    ZDB-ID 2037670-4
    ISSN 1545-293X ; 1527-8204
    ISSN (online) 1545-293X
    ISSN 1527-8204
    DOI 10.1146/annurev-genom-091212-153523
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  7. Article: Expansion of the RASopathies.

    Tidyman, William E / Rauen, Katherine A

    Current genetic medicine reports

    2016  Volume 4, Issue 3, Page(s) 57–64

    Abstract: The Ras/mitogen activated protein kinase (MAPK) pathway is essential in the regulation of cell cycle, differentiation, growth, cell senescence and apoptosis, all of which are critical to normal development. A class of neurodevelopmental disorders, ... ...

    Abstract The Ras/mitogen activated protein kinase (MAPK) pathway is essential in the regulation of cell cycle, differentiation, growth, cell senescence and apoptosis, all of which are critical to normal development. A class of neurodevelopmental disorders, RASopathies, is caused by germline mutations in genes of the Ras/MAPK pathway. Through the use of whole exome sequencing and targeted sequencing of selected genes in cohorts of panel-negative RASopathy patients, several new genes have been identified. These include:
    Language English
    Publishing date 2016-07-01
    Publishing country United States
    Document type Journal Article
    ISSN 2167-4876
    ISSN 2167-4876
    DOI 10.1007/s40142-016-0100-7
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  8. Article ; Online: Ras/MAPK dysregulation in development causes a skeletal myopathy in an activating Braf

    Maeda, Yoshiko / Tidyman, William E / Ander, Bradley P / Pritchard, Catrin A / Rauen, Katherine A

    Developmental dynamics : an official publication of the American Association of Anatomists

    2021  Volume 250, Issue 8, Page(s) 1074–1095

    Abstract: Background: Cardio-facio-cutaneous (CFC) syndrome is a human multiple congenital anomaly syndrome that is caused by activating heterozygous mutations in either BRAF, MEK1, or MEK2, three protein kinases of the Ras/mitogen-activated protein kinase (MAPK) ...

    Abstract Background: Cardio-facio-cutaneous (CFC) syndrome is a human multiple congenital anomaly syndrome that is caused by activating heterozygous mutations in either BRAF, MEK1, or MEK2, three protein kinases of the Ras/mitogen-activated protein kinase (MAPK) pathway. CFC belongs to a group of syndromes known as RASopathies. Skeletal muscle hypotonia is a ubiquitous phenotype of RASopathies, especially in CFC syndrome. To better understand the underlying mechanisms for the skeletal myopathy in CFC, a mouse model with an activating Braf
    Results: The activating Braf
    Conclusions: A skeletal myopathy was identified in the CFC Braf
    MeSH term(s) Alleles ; Animals ; Ectodermal Dysplasia/genetics ; Ectodermal Dysplasia/metabolism ; Ectodermal Dysplasia/pathology ; Facies ; Failure to Thrive/genetics ; Failure to Thrive/metabolism ; Failure to Thrive/pathology ; Heart Defects, Congenital/genetics ; Heart Defects, Congenital/metabolism ; Heart Defects, Congenital/pathology ; Mice ; Mitogen-Activated Protein Kinases/genetics ; Mitogen-Activated Protein Kinases/metabolism ; Muscle, Skeletal/metabolism ; Muscle, Skeletal/pathology ; Muscular Diseases/genetics ; Muscular Diseases/metabolism ; Muscular Diseases/pathology ; Phenotype ; Proto-Oncogene Proteins B-raf/genetics ; Proto-Oncogene Proteins B-raf/metabolism
    Chemical Substances Braf protein, mouse (EC 2.7.11.1) ; Proto-Oncogene Proteins B-raf (EC 2.7.11.1) ; Mitogen-Activated Protein Kinases (EC 2.7.11.24)
    Language English
    Publishing date 2021-02-13
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1102541-4
    ISSN 1097-0177 ; 1058-8388
    ISSN (online) 1097-0177
    ISSN 1058-8388
    DOI 10.1002/dvdy.309
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  9. Article ; Online: MEK-inhibitor-mediated rescue of skeletal myopathy caused by activating Hras mutation in a Costello syndrome mouse model

    William E. Tidyman / Alice F. Goodwin / Yoshiko Maeda / Ophir D. Klein / Katherine A. Rauen

    Disease Models & Mechanisms, Vol 15, Iss

    2022  Volume 2

    Abstract: Costello syndrome (CS) is a congenital disorder caused by heterozygous activating germline HRAS mutations in the canonical Ras/mitogen-activated protein kinase (Ras/MAPK) pathway. CS is one of the RASopathies, a large group of syndromes caused by ... ...

    Abstract Costello syndrome (CS) is a congenital disorder caused by heterozygous activating germline HRAS mutations in the canonical Ras/mitogen-activated protein kinase (Ras/MAPK) pathway. CS is one of the RASopathies, a large group of syndromes caused by mutations within various components of the Ras/MAPK pathway. An important part of the phenotype that greatly impacts quality of life is hypotonia. To gain a better understanding of the mechanisms underlying hypotonia in CS, a mouse model with an activating HrasG12V allele was utilized. We identified a skeletal myopathy that was due, in part, to inhibition of embryonic myogenesis and myofiber formation, resulting in a reduction in myofiber size and number that led to reduced muscle mass and strength. In addition to hyperactivation of the Ras/MAPK and PI3K/AKT pathways, there was a significant reduction in p38 signaling, as well as global transcriptional alterations consistent with the myopathic phenotype. Inhibition of Ras/MAPK pathway signaling using a MEK inhibitor rescued the HrasG12V myopathy phenotype both in vitro and in vivo, demonstrating that increased MAPK signaling is the main cause of the muscle phenotype in CS.
    Keywords costello syndrome ; hypotonia ; mek inhibitor ; myogenesis ; rasopathies ; ras/mapk ; Medicine ; R ; Pathology ; RB1-214
    Subject code 570
    Language English
    Publishing date 2022-02-01T00:00:00Z
    Publisher The Company of Biologists
    Document type Article ; Online
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  10. Article ; Online: Familial cardio-facio-cutaneous syndrome: Vertical transmission of the BRAF p.G464R pathogenic variant and review of the literature.

    Rauen, Katherine A / Maeda, Yoshiko / Egense, Alena / Tidyman, William E

    American journal of medical genetics. Part A

    2020  Volume 185, Issue 2, Page(s) 469–475

    Abstract: Cardio-facio-cutaneous syndrome (CFC) is one of the RASopathies and is caused by germline mutations that activate the Ras/mitogen-activated protein kinase (MAPK) pathway. CFC is due to heterozygous germline mutations in protein kinases BRAF, MEK1, or ... ...

    Abstract Cardio-facio-cutaneous syndrome (CFC) is one of the RASopathies and is caused by germline mutations that activate the Ras/mitogen-activated protein kinase (MAPK) pathway. CFC is due to heterozygous germline mutations in protein kinases BRAF, MEK1, or MEK2 and rarely in KRAS, a small GTPase. CFC is a multiple congenital anomaly disorder in which individuals may have craniofacial dysmorphia, heart issues, skin and hair anomalies, and delayed development. Pathogenic variants for CFC syndrome are usually considered de novo because vertical transmission has only been reported with MEK2 and KRAS. The index case was a 3-year-old male with features consistent with the clinical diagnosis of CFC. Sequencing revealed a previously reported heterozygous likely pathogenic variant BRAF p.G464R. Upon detailed family history, the index case's pregnant mother was noted to have similar features to her son. Targeted familial testing of the BRAF pathogenic variant was performed on the mother, confirming her diagnosis. Prenatal genetic testing for the fetus was declined, but postnatal molecular testing of the index case's sister was positive for the familial BRAF p.G464R variant. Functional analysis of the variant demonstrated increased kinase activity. We report the first identified vertically transmitted functional BRAF pathogenic variant. Our findings emphasize the importance of obtaining a comprehensive evaluation of family members and that activating pathogenic variants within the canonical MAPK cascade mediated by BRAF are compatible with human reproduction.
    MeSH term(s) Abnormalities, Multiple/genetics ; Abnormalities, Multiple/pathology ; Adult ; Child, Preschool ; Ectodermal Dysplasia/genetics ; Ectodermal Dysplasia/pathology ; Facies ; Failure to Thrive/genetics ; Failure to Thrive/pathology ; Female ; Genetic Predisposition to Disease ; Germ-Line Mutation/genetics ; Heart Defects, Congenital/genetics ; Heart Defects, Congenital/pathology ; Humans ; MAP Kinase Kinase 1/genetics ; MAP Kinase Kinase 2/genetics ; Male ; Pregnancy ; Proto-Oncogene Proteins B-raf/genetics ; Proto-Oncogene Proteins p21(ras)/genetics
    Chemical Substances KRAS protein, human ; MAP2K2 protein, human (EC 2.7.1.-) ; BRAF protein, human (EC 2.7.11.1) ; Proto-Oncogene Proteins B-raf (EC 2.7.11.1) ; MAP Kinase Kinase 1 (EC 2.7.12.2) ; MAP Kinase Kinase 2 (EC 2.7.12.2) ; MAP2K1 protein, human (EC 2.7.12.2) ; Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2)
    Language English
    Publishing date 2020-12-04
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2108614-X
    ISSN 1552-4833 ; 0148-7299 ; 1552-4825
    ISSN (online) 1552-4833
    ISSN 0148-7299 ; 1552-4825
    DOI 10.1002/ajmg.a.61995
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