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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pheochromacytoma is a relatively rare cause of arterial hypertension. Untreated pheochromacytoma may however lead to a fatal hypertensive crisis during anaesthesia or another form of stress. It is therefore important to correctly diagnose this disease. 24-hour monitoring of blood pressure (BP) can already contribute to the diagnosis of pheochromacytoma based on the frequent occurrence of BP variability and the absence of a night-time fall in BP. 5 gene mutations have so far been identified that may be responsible for the familial form of pheochromacytoma: mutation of the von Hippel-Lindau (VHL) gene, leading to the onset of VHL syndrome, mutation of the RET-proto-oncogene in multiple endocrine adenomatosis type 2, mutation of the type 1 gene for neurofibromatosis, which is associated with von Recklinghausen's disease and finally mutation of the genes encoding the B and D subunits of succinated hydrogenase (SDHB, SDHD), which are associated with familial paragangliomas and pheochromacytoma. Genetic analysis should therefore be carried out for all confirmed cases of pheochromacytoma, especially for young people under 50 years of age. Biochemical diagnostics relies mainly on measurements of free metanephrines in plasma or urine, which usually has greater diagnostic weight than plasma, or catecholamines in urine. The diagnosis of extraadrenal or multiple forms can use not only CT/MR but also imaging using the radiopharmaceutical 123I-Metaiodobenzylguanidine (MIBG) or 18F-fluorodopamine PET (only available in the USA). Pharmacological treatment using alpha or beta receptor blockers with subsequent laparoscopic excision of the tumor is usually successful in benign forms of pheochromocytoma. Unfortunately, there are still no convincingly effective therapeutic procedures available for malign forms.
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PMID:[Diagnostic and therapeutic procedures in pheochromocytoma: current trends]. 1757 79

Gastrointestinal stromal tumors (GISTs) may be caused by germline mutations of the KIT and platelet-derived growth factor receptor-alpha (PDGFRA) genes and treated by Imatinib mesylate (STI571) or other protein tyrosine kinase inhibitors. However, not all GISTs harbor these genetic defects and several do not respond to STI571 suggesting that other molecular mechanisms may be implicated in GIST pathogenesis. In a subset of patients with GISTs, the lesions are associated with paragangliomas; the condition is familial and transmitted as an autosomal-dominant trait. We investigated 11 patients with the dyad of 'paraganglioma and gastric stromal sarcoma'; in eight (from seven unrelated families), the GISTs were caused by germline mutations of the genes encoding subunits B, C, or D (the SDHB, SDHC and SDHD genes, respectively). In this report, we present the molecular effects of these mutations on these genes and the clinical information on the patients. We conclude that succinate dehydrogenase deficiency may be the cause of a subgroup of GISTs and this offers a therapeutic target for GISTs that may not respond to STI571 and its analogs.
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PMID:Clinical and molecular genetics of patients with the Carney-Stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDHC, and SDHD. 1766 67

von Hippel-Lindau disease, which is characterized by an increased risk of hemangioblastomas, clear cell renal carcinomas, and pheochromocytomas, is caused by inactivating mutations of the VHL tumor suppressor gene. The VHL gene product, pVHL, has multiple functions, but the best documented, and the one most clearly linked to tumor development, relates to its role as the substrate recognition module of a ubiquitin ligase complex that targets hypoxia-inducible factor (HIF) for destruction. pVHL function is often compromised in sporadic kidney cancers, and inhibitors of the HIF-responsive growth factor (vascular endothelial growth factor) are active against this disease. pVHL, by inhibiting atypical protein kinase C and hence JunB, also affects neuronal survival, as do the products of the other genes linked to familial pheochromocytoma or paraganglioma (NF1, RET, SDHB, SDHC, and SDHD). It is hypothesized that tumor-associated alleles of these genes allow primitive sympathoadrenal precursors to escape developmental culling, and that such cells are at increased risk of forming tumors.
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PMID:Von Hippel-Lindau disease. 1803 96

1. Recent clinical and fundamental research studies have revolutionized our understanding of the genetics of phaeochromocytoma (PH) and functional paraganglioma (FPGL). It was widely thought that only 10% of PH patients had familial disease and that the malignant phenotype of PH could not be diagnosed before occurrence of the first metastasis. 2. Human genetic studies have now shown that 25-30% of patients have hereditary PH due to a germline mutation in the SDHB, SDHD, VHL, RET or NF1 gene and that the identification of a germline SDHB mutation is associated with a high risk of malignancy and a poor prognosis in PH/PGL patients. 3. Fundamental research studies have shown that SDH genes are tumour suppressor genes and that succinate dehydrogenase inactivation induces abnormal stimulation of the hypoxia-angiogenesis pathway. 4. Finally various fundamental research studies, conducted through the Cortico and Medullo-surrenale: les Tumeurs Endocrines (COMETE) network in France and by other groups worldwide, have produced new recommendations for genetic counselling and testing and for the management of PH patients. They have also improved our understanding of the molecular mechanisms involved in PH tumorigenesis.
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PMID:Recent advances in the genetics of phaeochromocytoma and functional paraganglioma. 1830 24

Clinical and fundamental research based on the pheochromocytoma cohort of the COMETE network has drastically improved our knowledge of pheochromocytoma (PH). Previously, it was widely thought that only 10 % of PH patients had familial forms and that the malignant phenotype of PH could not be diagnosed before the first metastasis had already occurred. Genetic studies of the COMETE DNA collection contributed to showing that 25% to 30% of patients in fact have hereditary PH, due to a germline mutation of the SDHB, SDHD, VHL, RET or NF1 genes. The high-quality post-surgical clinical data collected by the COMETE network also show that SDHB germline mutations are a major risk factor for malignancy and poor outcome. Fundamental research work on the COMETE tumour collection shows that SDH genes are new tumour suppressor genes and that succinate dehydrogenase inactivation induces abnormal stimulation of the hypoxia-angiogenesis pathway. Since 2001, work by the COMETE network has led to new recommendations for genetic counselling and genetic testing in pheochromocytoma, and also for patient management. Finally, it has identified new molecular mechanisms involved in PH-related tumorigenesis.
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PMID:[Achievements of the COMETE program in the genetics of pheochromocytoma]. 1866 85

Familial renal cell carcinoma (RCC) is a heterogeneous disorder that is most commonly caused by germline mutations in the VHL, MET, and FLCN genes or by constitutional chromosome 3 translocations. However, for many patients with familial RCC, the genetic basis of the disease is undefined. We investigated whether germline mutations in fumarate hydratase (FH) or succinate dehydrogenase subunit genes (SDHB, SDHC, SDHD) were associated with RCC susceptibility in 68 patients with no clinical evidence of an RCC susceptibility syndrome. No mutations in FH, SDHC, or SDHD were identified in probands, but 3 of the 68 (4.4%) probands had a germline SDHB mutation. Patients with a germline SDHB mutation presented with familial RCC (n = 1) or bilateral RCC (n = 2) and no personal or family history of pheochromocytoma or head and neck paraganglioma. Age at diagnosis of RCC in SDHB mutation carriers ranged from 24 to 73 years. These findings 1) demonstrate that patients with suspected inherited RCC should be examined for germline SDHB mutations, 2) suggest that all identified SDHB mutation carriers should be offered surveillance for RCC, and 3) provide a further link between familial RCC and activation of hypoxic-gene response pathways.
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PMID:Germline SDHB mutations and familial renal cell carcinoma. 1872 80

Hereditary susceptibility to pheochromocytoma (PCC) and paraganglioma (PGL) represents a very complex genetic scenario. It has been reported that the absence of familial antecedents of the disease does not preclude the existence of a mutation affecting any of the five major susceptibility genes. In fact, 11-24% of apparently sporadic cases (without familial or syndromic antecedents) harbor an unexpected germline mutation, but we do not know what is happening in "truly apparently" sporadic patients (i.e., apparently sporadic cases diagnosed with only one tumor). In the present study, we have analyzed 135 apparently sporadic patients developing a single tumor for the five major susceptibility genes: VHL, RET, SDHB, SDHC, and SDHD. Fourteen percent of cases were found to harbor a germline mutation, and only 2.2% of patients were older than 45 years at onset. By taking into account the tumor location and a threshold age at onset of 45 years, we propose a rational scheme for genetic testing. Analyzing VHL and RET genes would be recommended only in young patients developing a single PCC. On the other hand, genetic testing of SDHD should be done in all patients developing an extra-adrenal tumor before the age of 45, and SDHC could be the responsible gene in cases developing a single head and neck tumor, independently of age. Finally, the analysis of SDHB should always be performed because of its association to malignancy and the low penetrance of mutations affecting this gene.
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PMID:Rationalization of genetic testing in patients with apparently sporadic pheochromocytoma/paraganglioma. 1934 21

The prevalence of germ line mutations within the RET-protooncogene and the tumor suppressor genes SDHB, SDHD, and VHL in pheochromocytomas (PC) varies in recent studies from 12 to 24%, if one look at them collectively. DNA was extracted from frozen tumor tissue as well as from blood leukocytes of 36 PC (26 sporadic/10 MEN2). Exons 1-8 of the SDHB-gene, 1-4 of the SDHD-gene, 1-3 of the VHL-gene, and exons 10, 11, 13, 14, 16 of the RET-gene were amplified by PCR and analyzed by DHPLC with the Transgenomic WAVE-System. Samples with aberrant wave profiles were subjected to direct sequencing. Genetic aberrations were correlated to clinical characteristics. Germ line mutations in sporadic PC were identified in four patients (11%) whereas somatic mutations were observed in two (5%) patients. Nine coding polymorphisms (PM) were identified in seven (19%) patients. Intronic variants were observed in six (17%) patients and were all located in the SHDB gene. Patients with wild type alleles in all assessed genes were older (53 vs. 37 years, P = 0.007) and presented with an increased tumor size (49 vs. 32 mm, P = 0.003) compared to patients with mutations. Malignant PC revealed multiple (>2) genetic alterations more frequently than benign PC (4/7 vs. 4/29, P = 0.03). Interestingly intronic variants of the SDHB gene occur more frequently in malignant than in benign PC (3/7 vs. 2/29, P = 0.04). The frequency of germ line mutations in sporadic pheochromocytomas was lower in our cohort than previously reported. Polymorphisms of the RET gene are common (17%) and occur in familial and sporadic PC. Multiple genetic alterations including mutations, polymorphisms and intronic variants are more frequently observed in malignant PC.
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PMID:Mutations and polymorphisms in the SDHB, SDHD, VHL, and RET genes in sporadic and familial pheochromocytomas. 1939 50

Pheochromocytomas/paragangliomas(PHEOs/PGLs) are rare but treacherous catecholamine-producing tumors which, if overlooked or improperly treated, will almost invariably prove fatal. Patients with MEN2 PHEOs have a high incidence of paroxysmal attacks and a higher prevalence of hypertension and other cardiovascular problems than do patients with Von-Hippel-Lindau (VHL) PHEOs. Compared to measurements of deconjugated metanephrines, plasma concentrations of free metanephrines are relatively independent of renal function and therefore more suitable for diagnosis of PHEO/PGL. Recently, the focus of Positron Emission Tomography (PET) imaging for these tumors has been the localization of PHEO. Although a limited number of studies are available, [18F]-fluorodopamine ([18F]DA) PET has been found to be the best overall imaging modality in the localization of PHEO. For adrenal PHEOs, this method seems to be comparable to other functional modalities such as [18F]-fluorodopa ([18F]DOPA) PET or [123I]-metaiodobenzylguanidine ([123I]MIBG)scintigraphy. For extraadrenal PHEOs, data are limited and more extensive studies are needed. In patients with metastatic PHEO, the sensitivity of [18F]DA PET is superior to [123I]MIBG. The so called "flip-flop" imaging showing superiority of non-specific [18F] flurodeoxyglucose (FDG) PET over specific [18F]DA PET has been described in rapidly progressive, often metastatic SDHB-associated PHEOs. Whether these data reflect PHEO cell dedifferentiation (e.g. losing Norepinephrine Transporter-NET) or increased metabolic rate remains to be established.
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PMID:Diagnosis of pheochromocytoma with special emphasis on MEN2 syndrome. 1957 Jul 38

Carney triad is a rare syndrome of unknown etiology characterized by having at least two out of three following neoplasms: gastrointestinal stromal tumor, pulmonary chondroma and extra-adrenal paraganglioma. About 100 cases have been reported worldwide. We report a case of Carney triad in a 42-year-old woman presented with a gastrointestinal stromal tumor in the stomach and a malignant functioning paraganglioma in the retroperitoneum that was fatal five years after diagnosis. The gastrointestinal stromal tumor was diagnosed as intermediate-risk of aggressive behavior and diffusely positive for c-kit whereas the retroperitoneal paraganglioma was negative for c-kit. Genetic analyses showed no mutations of KIT, PDGFRA, SDHB, SDHC, and SDHD genes in both tumors. To our best knowledge, this is the first case of Carney triad in Korea.
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PMID:Carney triad in an adult with aggressive behavior: the first case in Korea. 1988 77


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