Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.3.5.1 (succinate dehydrogenase)
 8,177 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Monogenic or single-gene forms of human hypertension result from mutations involving regulatory elements of the renin-angiotensin-aldosterone system (RAAS) or occur in syndromes associated with hereditary pheochromocytoma. RAAS gain-of-function mutations result in sodium retention, suppression of plasma renin activity, and often, but not invariably, hypokalemia. Hereditary RAAS syndromes result from intrinsic renal abnormalities (apparent mineralocorticoid excess and Liddle's syndromes) or from mineralocorticoid excess states (congenital adrenal hyperplasia and glucocorticoid-remediable aldosteronism). In the hereditary pheochromocytoma syndromes many asymptomatic individuals are identified because they are at-risk individuals in kindreds with a pheochromocytoma-predisposing syndrome. On the other hand, up to 25% of subjects with presumed "sporadic" pheochromocytoma have germline mutations in one of four pheochromocytoma susceptibility genes (the RET proto-oncogene, von Hippel-Lindau gene, neurofibromatosis F1 gene, and succinate dehydrogenase subunit D and succinate dehydrogenase subunit B genes). Hereditary pheochromocytomas are typically intra-adrenal and bilateral and patients typically present at younger ages compared with sporadic pheochromocytoma.
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PMID:Screening for genetic causes of hypertension. 1241 72

Hereditary pheochromocytomas and paragangliomas are caused by germline mutations in syndrome-associated genes. This includes multiple endocrine neoplasia Type 2 (MEN 2) caused by mutations in the RET proto-oncogene, von Hippel-Lindau (VHL) syndrome due to mutations of the VHL gene, neurofibromatosis Type I (NF1) caused by mutations of the NF1 gene, and pheochromocytoma/paraganglioma syndromes due to mutations in genes encoding the succinate dehydrogenase subunits D (SDHD) and B (SDHB). At the First International Symposium on Pheochromocytoma (ISP2005) organized by the National Institutes of Health, a panel of specialist clinicians and scientists from around the world addressed the topic of genetic testing in pheochromocytoma patients. This review summarizes the discussions and conclusions of the panel and provides a recommendation for evidence-based management of genetic testing in these patients and their families. A pragmatic algorithm is presented, taking into account patient age, tumor location (extra-adrenal, intra-adrenal, unilateral, and bilateral), biochemical presentation, and financial costs. This was based on cumulative frequencies ranging from 7.5% to 29% for germline mutations in four genes (RET, VHL, SDHB, and SDHD) in patients with apparently sporadic pheochromocytomas. This algorithm will need to be validated by further genetic analysis, multicenter studies, and long-term observations.
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PMID:Genetic testing in pheochromocytoma: increasing importance for clinical decision making. 1710 76

Mutations in the genes encoding succinate dehydrogenase (SDH) have been associated with susceptibility to pheochromocytoma. However, few reports have examined the level of SDH mRNAs expression. In this study, we examined the level of expression of mRNAs encoding SDHB, SDHC, and SDHD in pheochromocytoma, pheochromocytoma subgroups, and normal adrenal gland, and compared the expression of these genes to the level of expression of related genes in the same tissues. The mean relative level of expression of SDHB, SDHC, SDHD and VHL mRNA was 28.7+/-6.2%, 16.6+/-4.8%, 214+/-47.5% and 25.9+/-8.2%, respectively, in pheochromocytoma tissues compared to normal adrenal gland. Furthermore, the mean relative level of the RET proto-oncogene mRNA was 707+/-149% in pheochromocytoma compared to normal adrenal gland. The level of expression of the SDH genes was highly correlated in each individual sample (P<0.0001). The level of expression of the SDH mRNAs correlated with the level of VHL mRNA (P<0.0001), but not with the level of RET mRNA. The level of SDH mRNAs expression also correlated with the expression of phenylethanolamine N-methyl transferase (PNMT), an adrenaline synthesizing enzyme (P<0.01), which may explain the correlation between SDH expression and adrenaline content (P<0.05). The level of SDH mRNAs expression correlated strongly with the expression of VEGF mRNA (P<0.0001). In multiple endocrine neoplasia (MEN) 2a, the expression of the SDH genes and VHL mRNA was significantly higher than that observed in adrenal or extra-adrenal pheochromocytoma. The expression of the corticotropin-releasing hormone (CRH) mRNA was significantly higher in extra-adrenal pheochromocytoma than in adrenal pheochromocytoma or MEN2a. Thus, tumor-specific gene expression exists in pheochromocytoma, which may explain the characteristics of the tumor.
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PMID:Expression of mRNAs for succinate dehydrogenase subunits and related genes in pheochromocytoma. 1710 93

A 42-year old woman presented with headache, palpitation and facial flushing. Ultrasonograms and computed tomograms revealed tumors in both of the adrenal glands, anterior aspect of the inferior vena cava, and the right lobe of the thyroid gland. Fine needle aspiration biopsy of the thyroid nodule revealed papillary thyroid carcinoma. Serum calcitonin, CEA, intact PTH and calcium levels were within normal limits. Markedly elevated levels of urinary normetanephrine and vanillylmandelic acid, and the result of 131I-metaiodobenzylguanidine (131I-MIBG) scintigraphy indicated that both adrenal masses were pheochromocytoma. Bilateral adrenalectomy, paracaval mass removal and total thyroidectomy together with central lymph node dissection were performed. The final pathological diagnosis was bilateral adrenal pheochromocytoma, paraganglioma, papillary thyroid carcinoma and either parathyroid adenoma or hyperplasia. Analysis of the RET proto-oncogene mutation, von Hippel Lindau mutation, succinate dehydrogenase subunit B mutation, and succinate dehydrogenase subunit D mutation yielded negative results. The relationship of these lesions could not be determined. This is the first report of a combination of bilateral pheochromocytoma, abdominal paraganglioma, papillary thyroid carcinoma and either parathyroid adenoma or hyperplasia without hyperparathyroidism.
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PMID:Bilateral pheochromocytoma associated with paraganglioma and papillary thyroid carcinoma: report of an unusual case. 1726 67

Phaeochromocytoma is a rare clinical entity in children. Contrary to traditional teaching, which suggested that 10% of phaeochromocytomas are "familial", a germline mutation has been identified in up to 59% (27/48) of apparently sporadic phaeochromocytomas presenting at 18 years or younger and in 70% of those presenting before 10 years of age. The inherited predisposition may be attributable to a germline mutation in the Von Hippel-Lindau gene, the genes encoding the subunits B and D of succinate dehydrogenase, the RET proto-oncogene predisposing to multiple endocrine neoplasia type 2, or the neurofibromatosis type 1 gene. Of these, the Von Hippel-Lindau gene is the most commonly mutated gene in children presenting with a phaeochromocytoma. Genetic counselling is recommended before gene testing and investigation of the wider family. This review provides guidance on the aetiology, investigation, management, histopathology, genetics and follow-up of children with a phaeochromocytoma.
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PMID:Phaeochromocytoma in children. 1849 73

Although most pheochromocytomas (PCCs) and paragangliomas (PGLs) are sporadic, molecular genetic medicine has revealed that a considerable number of patients with apparently sporadic PCC actually have a genetic predisposition to the development of these tumors. After decades of intensive research, several genes are now known to play an important role in the pathogenesis of PCC. At present, these are RET proto-oncogene, von Hippel-Lindau disease tumor suppressor gene (VHL), neurofibromatosis type 1 tumor suppressor gene (NF1), genes encoding the succinate dehydrogenase (SDH) complex subunits SDHB, SDHC, and SDHD, but also SDHA, the gene encoding the enzyme responsible for the flavination of SDHA (SDHAF2 or hSDH5), and the newly described TMEM127 and MAX tumor suppressor genes. In addition to these ten PCC susceptibility genes, two other genes, KIF1B and PHD2, have also been associated with PCC. Studying the pathogenesis and the molecular correlation of these mutations has revealed the existence of two main transcription signatures: a pseudohypoxic cluster (VHL and SDH mutations) and a cluster rich in kinase receptor signaling and their downstream pathways (RET, NF1, TMEM127, and MAX mutations). However, the general mechanism in the pathogenesis of a syndrome does not entirely apply in the particular pathogenesis of PCC as a manifestation of that syndrome. A better understanding of the complexity and high genetic diversity of PCC and PGL may lead to more efficient diagnosis and management of the disease.
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PMID:Genetics and molecular pathogenesis of pheochromocytoma and paraganglioma. 2306 8