Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.12.2 (MEK)
18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cardiofaciocutaneous (CFC) syndrome is a condition of sporadic occurrence, with patients showing multiple congenital anomalies and mental retardation. It is characterised by failure to thrive, relative macrocephaly, a distinctive face with prominent forehead, bitemporal constriction, absence of eyebrows, hypertelorism, downward-slanting palpebral fissures often with epicanthic folds, depressed nasal root and a bulbous tip of the nose. The cutaneous involvement consists of dry, hyperkeratotic, scaly skin, sparse and curly hair, and cavernous haemangiomata. Most patients have a congenital heart defect, most commonly pulmonic stenosis and hypertrophic cardiomyopathy. The developmental delay usually is moderate to severe. The syndrome is caused by gain-of-function mutations in four different genes BRAF, KRAS, mitogen-activated protein/extracellular signal-regulated kinase MEK1 and MEK2, all belonging to the same RAS-extracellular signal-regulated kinase (ERK) pathway that regulates cell differentiation, proliferation and apoptosis. The CFC syndrome is a member of a family of syndromes that includes the Noonan and Costello syndromes, presenting with phenotypic similarities. Noonan syndrome is caused by mutations in the protein tyrosine phosphatase SHP-2 gene (PTPN11), with a few people having a mutation in KRAS. Costello syndrome is caused by mutations in HRAS. The protein products of these genes also belong to the RAS-ERK pathway. Thus, the clinical overlap of these three conditions, which often poses a problem of differential diagnosis, is explained by their pathogenetic relatedness.
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PMID:The cardiofaciocutaneous syndrome. 1682 33

The Ras signaling pathway controls important cellular responses to growth factors, and somatic mutations in RAS genes and other components of the Ras pathway, such as PTPN11 (encoding the protein-tyrosine phosphatase SHP-2) and BRAF, are found in human malignancies. Ras proteins are guanosine nucleotide-binding proteins that cycle between active guanosine triphosphate (GTP)-bound and inactive guanosine diphosphate (GDP)-bound conformations. Neoplasia-associated Ras mutations frequently affect amino acids G12, G13, or Q61 and decrease the intrinsic guanosine triphosphatase (GTPase) activity by ten- to twentyfold. The GTPase activity is crucial for Ras inactivation by hydrolysis and release of a phosphate group from Ras.GTP to produce Ras.GDP. We and others have recently discovered germline mutations in the KRAS gene in individuals diagnosed with Noonan and cardio-facio-cutaneous (CFC) syndrome, two clinically overlapping disorders characterized by short stature, distinct facial anomalies, heart defects, and other abnormalities. Noonan syndrome-associated mutations V14I and T58I K-Ras activate Ras but have milder biochemical effects than somatic mutations encountered in cancers, offering an explanation why these K-Ras lesions are tolerated during embryonic development. Together with recent findings of BRAF, MEK1, and MEK2 mutations in CFC syndrome and HRAS mutations in Costello syndrome, another clinically related disorder, it has now become clear that Noonan-like features (short stature, relative macrocephaly, facial anomalies, learning difficulties) that are found in these three related disorders are a result of constitutive activation of the Ras-Raf-extracellular signal-regulated and mitogen-activated protein kinase pathway.
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PMID:An unexpected new role of mutant Ras: perturbation of human embryonic development. 1721 12

Cardio-facio-cutaneous (CFC) syndrome is a multiple congenital anomaly/mental retardation syndrome characterized by heart defects, a distinctive facial appearance, ectodermal abnormalities and mental retardation. Clinically, it overlaps with both Noonan syndrome and Costello syndrome, which are caused by mutations in two genes, PTPN11 and HRAS, respectively. Recently, we identified mutations in KRAS and BRAF in 19 of 43 individuals with CFC syndrome, suggesting that dysregulation of the RAS/RAF/MEK/ERK pathway is a molecular basis for CFC syndrome. The purpose of this study was to perform comprehensive mutation analysis in 56 patients with CFC syndrome and to investigate genotype-phenotype correlation. We analyzed KRAS, BRAF, and MAP2K1/2 (MEK1/2) in 13 new CFC patients and identified five BRAF and one MAP2K1 mutations in nine patients. We detected one MAP2K1 mutation in three patients and four new MAP2K2 mutations in four patients out of 24 patients without KRAS or BRAF mutations in the previous study [Niihori et al., 2006]. No mutations were identified in MAPK3/1 (ERK1/2) in 21 patients without any mutations. In total, 35 of 56 (62.5%) patients with CFC syndrome had mutations (3 in KRAS, 24 in BRAF, and 8 in MAP2K1/2). No significant differences in clinical manifestations were found among 3 KRAS-positive patients, 16 BRAF-positive patients, and 6 MAP2K1/2-positive patients. Wrinkled palms and soles, hyperpigmentation and joint hyperextension, which have been commonly reported in Costello syndrome but not in CFC syndrome, were observed in 30-40% of the mutation-positive CFC patients, suggesting a significant clinical overlap between these two syndromes.
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PMID:Molecular and clinical characterization of cardio-facio-cutaneous (CFC) syndrome: overlapping clinical manifestations with Costello syndrome. 1736 77

Cardio-facio-cutaneous (CFC) syndrome is a multiple congenital anomaly/mental retardation syndrome characterized by a distinctive facial appearance, ectodermal abnormalities, and heart defects. Clinically, it overlaps with both Noonan syndrome and Costello syndrome, which are caused by mutations in 2 genes that encode molecules of the RAS/MAPK (mitogen activated protein kinase) pathway (PTPN11 and HRAS, respectively). Recently, mutations in KRAS, BRAF, and MEK1/2 have been identified in patients with CFC syndrome. Somatic mutations in KRAS and BRAF have been identified in various tumors. In contrast, the association with malignancy has not been noticed in CFC syndrome. Here we report a 9-year-old boy diagnosed with CFC syndrome and acute lymphoblastic leukemia. Sequencing analysis of the entire coding region of KRAS and BRAF showed a de novo germline BRAF E501G (1502A-->G) mutation. Molecular diagnosis and careful observations should be considered in children with CFC syndrome because they have germline mutations in proto-oncogenes and might develop malignancy.
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PMID:Leukemia in Cardio-facio-cutaneous (CFC) syndrome: a patient with a germline mutation in BRAF proto-oncogene. 1748 2

The p21 RAS subfamily of small GTPases, including KRAS, HRAS, and NRAS, regulates cell proliferation, cytoskeletal organization, and other signaling networks, and is the most frequent target of activating mutations in cancer. Activating germline mutations of KRAS and HRAS cause severe developmental abnormalities leading to Noonan, cardio-facial-cutaneous, and Costello syndrome, but activating germline mutations of NRAS have not been reported. Autoimmune lymphoproliferative syndrome (ALPS) is the most common genetic disease of lymphocyte apoptosis and causes autoimmunity as well as excessive lymphocyte accumulation, particularly of CD4(-), CD8(-) alphabeta T cells. Mutations in ALPS typically affect CD95 (Fas/APO-1)-mediated apoptosis, one of the extrinsic death pathways involving TNF receptor superfamily proteins, but certain ALPS individuals have no such mutations. We show here that the salient features of ALPS as well as a predisposition to hematological malignancies can be caused by a heterozygous germline Gly13Asp activating mutation of the NRAS oncogene that does not impair CD95-mediated apoptosis. The increase in active, GTP-bound NRAS augments RAF/MEK/ERK signaling, which markedly decreases the proapoptotic protein BIM and attenuates intrinsic, nonreceptor-mediated mitochondrial apoptosis. Thus, germline activating mutations in NRAS differ from other p21 Ras oncoproteins by causing selective immune abnormalities without general developmental defects. Our observations on the effects of NRAS activation indicate that RAS-inactivating drugs, such as farnesyltransferase inhibitors should be examined in human autoimmune and lymphocyte homeostasis disorders.
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PMID:NRAS mutation causes a human autoimmune lymphoproliferative syndrome. 1751 60

Because Cardio-facio-cutaneous (CFC) syndrome has significant phenotypic overlap with Costello syndrome, it may be difficult to establish the diagnosis on a clinical basis. The recent discoveries of germline HRAS mutations in patients with Costello syndrome and mutations in BRAF, MEK1, and MEK2 in CFC syndrome uncovered the biologic mechanism for the shared phenotypic findings based on the close interaction of the affected gene products within the MAP kinase pathway. We evaluated a series of patients who were either clinically diagnosed with Costello syndrome, or in whom the diagnoses of both Costello and CFC syndromes were considered. After excluding mutations in HRAS, we identified eight changes in BRAF and five in MEK1. Five mutations are novel, and all changes occurred de novo among those triads tested. A review of the clinical abnormalities showed important differences between patients with either a BRAF or MEK1 mutation, and those previously reported with an HRAS mutation. Statistical significance was achieved, despite the relatively small number of patients with BRAF and MEK1 mutations reported here, for polyhydramnios, growth hormone deficiency and the presence of more than one papilloma, which were less common in CFC compared to HRAS mutation positive patients. Although both CFC and Costello syndrome are characterized by cardiac abnormalities in about three-fourths of patients, the pattern of congenital heart defects (CHD), hypertrophic cardiomyopathy (HCM), and tachycardia differs somewhat. CHD, especially pulmonic stenosis associated with a secundum-type atrial septal defect, are more common in CFC than Costello syndrome (P = 0.02). Atrial tachycardia is less frequent in CFC patients with BRAF or MEK1 mutations, compared to Costello syndrome patients with HRAS mutation (P = 0.04). Chaotic atrial rhythm or multifocal atrial tachycardia was observed only in Costello syndrome. Malignant tumors have been viewed as characteristic for Costello syndrome due to HRAS mutations, however, we report here on a MEK1 mutation in a patient with a malignant tumor, a hepatoblastoma. Although this indicates that the presence of a tumor is not specific for Costello syndrome with HRAS mutation, it is noteworthy that the tumor histology differs from those commonly seen in Costello syndrome. Based on these clinical differences we suggest that patients with BRAF and MEK mutations should be diagnosed with CFC syndrome, and the diagnosis of Costello syndrome be reserved for patients with HRAS mutations.
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PMID:Further delineation of the phenotype resulting from BRAF or MEK1 germline mutations helps differentiate cardio-facio-cutaneous syndrome from Costello syndrome. 1755 24

Cardio-facio-cutaneous syndrome (CFC) and Costello syndrome (CS) are disorders with an overlapping spectrum of congenital anomalies. Mutations in the RAS-MAPK pathway have recently been reported in both of these syndromes, with HRAS mutations characteristic for CS and BRAF and MEK1/2 mutations for CFC. We report on a 3-year-old boy who underwent a cardiac transplant at age 8 months for hypertrophic cardiomyopathy; he was subsequently suspected to have CS. At age 35 months he presented with an intra-cardiac mass that was diagnosed as metastatic hepatoblastoma. Although hepatoblastoma is not known to have an increased frequency in immunocompromised patients, questions were raised as whether the post-transplant immuno-suppressive therapy played a role in tumor development. The patient died shortly thereafter and his post-mortem DNA analysis revealed a MEK1 mutation (Y130C) previously reported in CFC. While CS is associated with increased cancer risk, only a single case of leukemia has been reported in a patient with CFC, making this the first case of a solid tumor reported in a patient with CFC.
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PMID:Hepatoblastoma and heart transplantation in a patient with cardio-facio-cutaneous syndrome. 1756 82

Noonan syndrome (NS) is a congenital abnormality that affects multiple parts of the body. Approximately 50% of cases are caused by mutations in the PTPN11 gene. NS shares many clinical features with a group of developmental disorders including Costello syndrome and cardio-facio-cutaneous (CFC) syndrome. Recently, KRAS and SOS1 were identified as causative genes for NS. Moreover, mutations in several genes associated with the Ras-mitogen-activated protein kinase (MAPK) pathway, including HRAS, BRAF, MEK1, and MEK2 were identified in patients with Costello syndrome and CFC syndrome. Accordingly, this study carried out mutation analysis of nine genes including PTPN11, SOS1, GRB2, KRAS, HRAS, NRAS, BRAF, MEK1, and MEK2 associated with the Ras-MAPK pathway in 14 Korean patients with NS. Seven patients were found to have mutations in the PTPN11 gene. Mutation analyses of the other genes did not reveal any disease causing mutations except for one unclassified variation in the 3'-untranslated region of the HRAS gene (c.*1C>T). The patient's father also had the same substitution with the normal phenotype. Therefore, this variation is believed to be either a rare polymorphism or a disease-related variation with variable penetrance. The Ras-MAPK pathway has now emerged as a key cascade in a group of similar developmental disorders as well as in many types of cancers. This study found that, with the exception of PTPN11, mutations in genes related to the Ras-MAPK pathway appear to be uncommon, at least in Korean patients with NS.
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PMID:Mutation analysis of the genes involved in the Ras-mitogen-activated protein kinase (MAPK) pathway in Korean patients with Noonan syndrome. 1766 20

Cardio-facio-cutaneous (CFC) syndrome, Noonan syndrome (NS), and Costello syndrome (CS) are clinically related developmental disorders that have been recently linked to mutations in the RAS/MEK/ERK signalling pathway. This study was a mutation analysis of the KRAS, BRAF, MEK1 and MEK2 genes in a total of 130 patients (40 patients with a clinical diagnosis of CFC, 20 patients without HRAS mutations from the French Costello family support group, and 70 patients with NS without PTPN11 or SOS1 mutations). BRAF mutations were found in 14/40 (35%) patients with CFC and 8/20 (40%) HRAS-negative patients with CS. KRAS mutations were found in 1/40 (2.5%) patients with CFC, 2/20 (10%) HRAS-negative patients with CS and 4/70 patients with NS (5.7%). MEK1 mutations were found in 4/40 patients with CFC (10%), 4/20 (20%) HRAS-negative patients with CS and 3/70 (4.3%) patients with NS, and MEK2 mutations in 4/40 (10%) patients with CFC. Analysis of the major phenotypic features suggests significant clinical overlap between CS and CFC. The phenotype associated with MEK mutations seems less severe, and is compatible with normal mental development. Features considered distinctive for CS were also found to be associated with BRAF or MEK mutations. Because of its particular cancer risk, the term "Costello syndrome" should only be used for patients with proven HRAS mutation. These results confirm that KRAS is a minor contributor to NS and show that MEK is involved in some cases of NS, demonstrating a phenotypic continuum between the clinical entities. Although some associated features appear to be characteristic of a specific gene, no simple rule exists to distinguish NS from CFC easily.
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PMID:Cardio-facio-cutaneous and Noonan syndromes due to mutations in the RAS/MAPK signalling pathway: genotype-phenotype relationships and overlap with Costello syndrome. 1770 60

The RAS proteins and their downstream pathways play pivotal roles in cell proliferation, differentiation, survival and cell death, but their physiological roles in human development had remained unknown. Noonan syndrome, Costello syndrome, and cardio-facio-cutaneous (CFC) syndrome are autosomal dominant multiple congenital anomaly syndromes characterized by a distinctive facial appearance, heart defects, musculocutaneous abnormalities, and mental retardation. A variety of mutations in protein tyrosine phosphatase, non-receptor type 11(PTPN11) has been identified in 50% of Noonan patients. Specific mutations in PTPN11 have been identified in LEOPARD (multiple lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness) syndrome. In 2005, we discovered Harvey-RAS (HRAS) germline mutations in patients with Costello syndrome. This discovery provided a clue to identification of germline mutations in Kirsten-RAS (KRAS), BRAF and mitogen-activated protein kinase kinase 1 and 2 (MAP2K1/MAP2K2) in patients with CFC syndrome. These genes encode molecules in the RAS/RAF/MEK/extracellular signal-regulated kinase (ERK) pathway, leading to a new concept that clinically related disorders, i.e., Noonan, Costello, and CFC syndromes are caused by dysregulation of the RAS/mitogen activated protein kinase (MAPK) pathway. In the present review, we summarize mutations in HRAS, KRAS, BRAF, MAP2K1/2, and PTPN11, the phenotypes of patients with these mutations, the functional properties of mutants and animal models. Finally we suggest that disorders with mutations of molecules in the RAS/MAPK cascade (Noonan, LEOPARD, Costello, and CFC syndromes and neurofibromatosis type I) may be comprehensively termed "the RAS/MAPK syndromes." Details on mutations will be updated in the RAS/MAPK Syndromes Homepage (www.medgen.med.tohoku.ac.jp/RasMapk syndromes.html).
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PMID:The RAS/MAPK syndromes: novel roles of the RAS pathway in human genetic disorders. 1847 Sep 43


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