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:1.3.5.1 (succinate dehydrogenase)
8,177 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To evaluate the prevalence of succinate dehydrogenase (SDH) B, C, and D germline mutations in a surgical series of cervical paragangliomas and to precise the characteristics of patients presenting with familial form. Among 29 patients operated on cervical paragangliomas (carotid or vagal body) at our institution between 1994 and 2007, 23 could be asked for a genetic analysis and a familial study. Clinical characteristics of patients harboring a germline SDH mutation were studied and compared with those presenting without mutation. Mutations were found in 8/23 (35%) patients, mostly in SDHD gene (6 cases), and in SDHB and SDHC gene, respectively, in one case each. Mean age at onset was significantly lower for patients with mutation (34 vs. 51.5 years, P = 0.01). In patients presenting with a mutation, 50% had a family history of paraganglioma compared with 0% for others (P = 0.008) and 87.5% had a multifocal form of paragangliomas versus 0% for others (P = 0.001). No difference was found concerning malignant forms between the two groups (12.5 vs. 13.3%). In the 16 patients who had an apparently sporadic paraganglioma, 6% had mutations in the SDH gene. A positive family history of paraganglioma and/or the presence of bilateral or multiple paragangliomas and/or an early age of onset are the main parameters associated with SDH mutations. Genetic testing should be considered for all patients with a cervical paraganglioma, even for those presenting with an apparently sporadic tumor as familial form may be such identified in 6% of cases.
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PMID:Cervical paragangliomas: is SDH genetic analysis systematically required? 1798 8

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

Recently, nuclear genes encoding two mitochondrial complex II subunit proteins, SDHD and SDHB, have been found to be associated with the development of familial pheochromocytomas and paragangliomas (hereditary pheochromocytoma/paraganglioma syndrome: HPPS). Growing evidence suggests that a mutation of SDHB is highly associated with abdominal (or thoracic) paraganglioma and the following distant metastasis (malignant paraganglioma). Previously, we identified a novel heterozygous G to A point mutation at the first base of intron 3 of the SDHB gene (IVS3+1G>A) in a malignant abdominal paraganglioma from a Japanese patient. In the present study, we report another case of SDHB mutation (R46Q) in a Japanese patient with both abdominal and thoracic paraganglioma following malignant metastasis. In addition, we identified an asymptomatic carrier of SDHB mutation in this family. Our report highlights the pathogenic role of the SDHB mutation (R46Q) in malignant paraganglioma. We also discuss the desired protocol that should be adopted to follow up an asymptomatic carrier of this mutation.
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PMID:R46Q mutation in the succinate dehydrogenase B gene (SDHB) in a Japanese family with both abdominal and thoracic paraganglioma following metastasis. 1836 51

Germline mutations in the genes encoding the B (SDHB) and D (SDHD) subunits of the heterotetrameric protein succinate dehydrogenase (mitochondrial complex II) are important causes of inherited and apparently sporadic paragangliomas. In an effort to further investigate the role of these genes in malignant sympathetic paragangliomas and adrenal pheochromocytomas, we screened a series of tumors for mutations in SDHB and SDHD. Mutation testing was performed on DNA extracted from formalin-fixed, paraffin-embedded tumors and associated normal tissues by polymerase chain reaction amplification and direct sequencing of the coding regions and intron-exon junctions of the SDHB and SDHD genes. Among 16 malignant paragangliomas with proven metastases, 6 (38%) had mutations in SDHB (2 nonsense, 1 splice site, 1 insertion causing a frameshift, and 2 presumably deleterious missense mutations). Probable deleterious SDHB variants were also detected in 5 (45%) of 11 paragangliomas without known metastatic disease (1 splice site, 1 deletion causing a frameshift, and 3 missense changes). In 12 malignant pheochromocytomas, 1 SDHD and no SDHB mutations were identified. The identical SDHB mutation was detected in DNA extracted from accompanying normal tissue for each of the 10 cases on which this analysis was performed. An excess of SDHB mutations in paragangliomas versus pheochromocytomas was found, with no difference in the frequency of mutations in malignant versus benign paragangliomas. The disparate mutational spectra in malignant paragangliomas and pheochromocytomas may reflect differences in underlying tumor biology.
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PMID:Germline SDHB mutations are common in patients with apparently sporadic sympathetic paragangliomas. 1838 70

Recently, enzymes of the tricarboxylic acid (TCA) cycle have emerged as novel tumor suppressors. In particular, mutations in the nuclear-encoded subunits of succinate dehydrogenase (SDHB, SDHC, and SDHD) cause paragangliomas and pheochromocytomas. Although the mechanism(s) by which disruption of mitochondrial metabolism leads to neoplasia is largely unknown, increasing evidence points to an activation of pseudohypoxia. In this study, we have shown that silencing of SDHB using DNA-based small interfering RNA resulted in major impairments in cellular proliferation, respiration, and a corresponding shift to glycolysis. The levels of reactive oxygen species, however, were unchanged. As expected, hypoxia-inducible factor-1 alpha (HIF-1 alpha) and HIF-2alpha were up-regulated in chronically silenced cells, suggesting that a pseudohypoxic state was attained. In addition, the c-Jun amino-terminal kinase and p38 kinase stress signaling proteins were hyperphosphorylated in SDHB-silenced cells. Microarray analysis showed that >400 genes were influenced (6-fold or more up-regulation or down-regulation) by silencing of SDHB, confirming the importance of the TCA cycle in cellular metabolism. Examples of dysregulated genes included those involved in proliferation, adhesion, and the hypoxia pathway. Of interest, SDHB-silenced cells had a greater capacity to adhere to extracellular matrix components, including fibronectin and laminin, than control cells, thus suggesting a possible mechanism of tumor initiation. Although transient silencing of the HIF-1 alpha transcription factor in SDHB-silenced cells had little effect on the expression of a subset of up-regulated genes, it partially reversed the adhesion phenotype to fibronectin, pointing to a potentially important role for HIF-1 in this process.
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PMID:Cells silenced for SDHB expression display characteristic features of the tumor phenotype. 1851 64

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

Individuals with PTEN mutations have Cowden syndrome (CS), associated with breast, thyroid, and endometrial neoplasias. Many more patients with features of CS, not meeting diagnostic criteria (termed CS-like), are evaluated by clinicians for CS-related cancer risk. Germline mutations in succinate dehydrogenase subunits SDHB-D cause pheochromocytoma-paraganglioma syndrome. One to five percent of SDHB/SDHD mutation carriers have renal cell or papillary thyroid carcinomas, which are also CS-related features. SDHB-D may be candidate susceptibility genes for some PTEN mutation-negative individuals with CS-like cancers. To address this hypothesis, germline SDHB-D mutation analysis in 375 PTEN mutation-negative CS/CS-like individuals was performed, followed by functional analysis of identified SDH mutations/variants. Of 375 PTEN mutation-negative CS/CS-like individuals, 74 (20%) had increased manganese superoxide dismutase (MnSOD) expression, a manifestation of mitochondrial dysfunction. Among these, 10 (13.5%) had germline mutations/variants in SDHB (n = 3) or SDHD (7), not found in 700 controls (p < 0.001). Compared to PTEN mutation-positive CS/CS-like individuals, those with SDH mutations/variants were enriched for carcinomas of the female breast (6/9 SDH versus 30/107 PTEN, p < 0.001), thyroid (5/10 versus 15/106, p < 0.001), and kidney (2/10 versus 4/230, p = 0.026). In the absence of PTEN alteration, CS/CS-like-related SDH mutations/variants show increased phosphorylation of AKT and/or MAPK, downstream manifestations of PTEN dysfunction. Germline SDH mutations/variants occur in a subset of PTEN mutation-negative CS/CS-like individuals and are associated with increased frequencies of breast, thyroid, and renal cancers beyond those conferred by germline PTEN mutations. SDH testing should be considered for germline PTEN mutation-negative CS/CS-like individuals, especially in the setting of breast, thyroid, and/or renal cancers.
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PMID:Germline mutations and variants in the succinate dehydrogenase genes in Cowden and Cowden-like syndromes. 2156 94

Head and neck paragangliomas are usually asymptomatic and benign tumours arising mainly from the carotid body and the vagal, tympanic or jugular glomus. The majority of patients develop sporadic masses, and around 30% of cases harbour germline mutations in one of the succinate dehydrogenase genes: SDHB, SDHC or SDHD. In these hereditary cases, the presence of familial antecedents of the disease, multiplicity/bilaterality, young age at onset, and more recently, presence of gastrointestinal stromal tumours, are main factors to be considered. Here we describe a new mutation (c.256-257insTTT) affecting the SDHC gene in a 60-year-old-patient with a single head and neck paraganglioma, and without familial antecedents of the disease. In silico splice site analysis showed that this variant created a cryptic splice acceptor site and loss of heterozygosity (LOH) supported the pathogenic role of the mutation. Control population analyses did not detect this variant but revealed a novel SDHC polymorphism that exhibited a frequency of 0.3% (3/1020). This latter finding highlights the importance of assessing the clinical relevance of variants of unknown significance by means of analysing sufficient controls. Despite having found a germline mutation in an older, apparently sporadic patient, we consider that the high costs of analysing all susceptibility genes related to the disease support the recommendation of screening for mutations only in patients fulfilling the above criteria.
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PMID:SDHC mutation in an elderly patient without familial antecedents. 1868 55

Iron is an essential nutrient that participates as a redox co-factor in a broad range of cellular processes. In response to iron deficiency, the budding yeast Saccharomyces cerevisiae induces the expression of the Cth1 and Cth2 mRNA-binding proteins to promote a genome-wide remodeling of cellular metabolism that contributes to the optimal utilization of iron. Cth1 and Cth2 proteins bind to specific AU-rich elements within the 3'-untranslated region of many mRNAs encoding proteins involved in iron-dependent pathways, thereby promoting their degradation. Here, we show that the DEAD box Dhh1 helicase plays a crucial role in the mechanism of Cth2-mediated mRNA turnover. Yeast two-hybrid experiments indicate that Cth2 protein interacts in vivo with the carboxyl-terminal domain of Dhh1. We demonstrate that the degradation of succinate dehydrogenase SDH4 mRNA, a known target of Cth2 on iron-deficient conditions, depends on Dhh1. In addition, we localize the Cth2 protein to cytoplasmic processing bodies in strains defective in the 5' to 3' mRNA decay pathway. Finally, the degradation of trapped SDH4 mRNA intermediates by Cth2 supports the 5' to 3' directionality of mRNA turnover. Taken together, these results suggest that Cth2 protein recruits the Dhh1 helicase to ARE-containing mRNAs to promote mRNA decay.
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PMID:The Cth2 ARE-binding protein recruits the Dhh1 helicase to promote the decay of succinate dehydrogenase SDH4 mRNA in response to iron deficiency. 1871 69

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


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