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)

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

Pheochromocytoma (PHEO) is considered to be a rare cause of hypertension. However, if left untreated, PHEOs may lead to fatal hypertensive crises during anesthesia and other stresses. The diagnosis of PHEO is therefore extremely important. A 24-hour blood pressure (BP) pattern per se might be of some diagnostic value due to frequently observed higher BP variability as well as an attenuated night-time BP decrease. So far, germline mutations in five genes have been identified to be responsible for familial PHEOs: the von Hippel-Lindau gene, which causes von Hippel-Lindau syndrome, the RET gene leading to multiple endocrine neoplasia type 2, the neurofibromatosis type 1 gene, which is associated with von Recklinghausen's disease and the genes encoding the B and D subunits of mitochondrial succinate dehydrogenase (SDHB, SDHD), which are associated with familial paragangliomas and PHEOs. Genetic analysis should be offered to those patients with confirmed PHEO who are 50 years old or younger. Plasma-free metanephrines or urinary fractionated metanephrines seem to have higher diagnostic values compared to plasma or urinary catecholamines for the biochemical diagnosis of PHEO. Imaging with (123)I-metaiodobenzylguanidine or (18)F-fluorodopamine PET, if available, are in addition to CT/MRI useful for the detection of multifocal/extra-adrenal forms. Appropriate pharmacologic treatment with subsequent laparoscopic extirpation of PHEO is usually successful in benign forms. There is, however, no convincingly effective mode of treatment in malignant PHEOs.
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PMID:Recent advances in the diagnosis and treatment of pheochromocytoma. 1711 41

Familial head and neck paragangliomas account for approximately 10% of all head and neck paragangliomas. There are three known genes associated with genetic susceptibility to head and neck paragangliomas: succinate dehydrogenase complex subunit 'D', 'B' and 'C' (SDHD, SDHB and SDHC). The genes most frequently implicated: SDHD and SDHB, also predispose to phaeochromocytoma. SDHD shows a complex inheritance pattern - tumours do not develop if the mutation is inherited from the mother. SDHB mutations are associated with malignant phaeochromocytoma. Patients who present with a family history of paraganglioma or phaeochromocytoma, with multiple tumours, or early onset tumours (<50 years), should be referred for genetic investigation.
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PMID:The genetics of paragangliomas: a review. 1765 Dec 79

Evaluation of the possible implication of the SDHA, SDHB, SDHC, SDHD and CS genes in non-obstructive male infertility was performed on the basis that sperm concentration in the ejaculate has been previously correlated with nuclear-encoded mitochondrial enzyme activities (the four subunits of succinate dehydrogenase/complex II of the respiratory chain and citrate synthase). We performed an exhaustive analysis of the five genes for the presence of sequence variants that could be associated with impairment of sperm production. blastn searches in the genomic sequence NCBI database evidenced the presence of highly homologous sequences elsewhere on the genome that can interfere with polymerase chain reaction experiments. Therefore, a careful design of the analytical strategy to search for sequence variants was performed. In this report, we provide primer sequences that allowed selective amplification of coding and immediate flanking regions of the five genes. Fifty-five sequence variations in the five genes were identified in infertile and normozoospermic fertile individuals as controls and only one of them (SDHA c.456+32G>A) showed significant genotype association with impairment of sperm production. Moreover, new single nucleotide polymorphisms identified should be useful in future association studies for other human diseases related to nuclear-encoded genes, leading to mitochondrial respiratory chain activity impairment revealing the physiological role of these genes.
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PMID:Single nucleotide polymorphisms in succinate dehydrogenase subunits and citrate synthase genes: association results for impaired spermatogenesis. 1729 51

The SDHA, SDHB, SDHC, and SDHD genes code for subunits of succinate dehydrogenase (SDH), which forms part of the mitochondrial respiratory chain. Germline mutations in the genes encoding SDHB and SDHD have been reported in familial paragangliomas/pheochromocytomas and in apparently sporadic pheochromocytomas. SDHB and SDHD mutations are widely distributed along the genes with no apparent hot spots. SDHB mutations are often detected in malignant and extra-adrenal pheochromocytomas. SDHD mutations are also detected frequently in head and neck paragangliomas. We sequenced the entire coding regions of the SDHB and SDHD genes in 17 pheochromocytomas. We identified novel heterozygous G to A point mutations at the first base of intron 3 of the SDHB gene in a malignant extra-adrenal abdominal pheochromocytoma patient, and at the first base of codon 111 of the SDHD gene in an adrenal pheochromocytoma patient. Further, we confirmed the SDHD mutation by DHPLC. The prevalence of SDHB and SDHD mutations in pheochromocytomas we examined was 12% (2/17). Thus, we identified two novel SDH mutations in Japanese pheochromocytomas. Further studies will investigate the oncogenic potential of these mutations.
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PMID:Novel germline mutations in the SDHB and SDHD genes in Japanese pheochromocytomas. 1730 34

Paraganglioma are rare tumours, which develop in the paraganglionic sites of the head and the neck, and around the medulla of the adrenal gland and the sympathetic ganglions of the thoracoabdominal and pelvic regions. Their morbidity-mortality is due to the local and regional spread to the adjacent nervous and vascular structures, their hypervascularisation, the major cardiovascular complications when they are secreting tumours and the risk of recurrences and metastases. Paraganglioma can secrete catecholamines. The only curative treatment is surgical exeresis. The hereditary paraganglioma are more often multifocal, recurrent, sometimes malignant, and with an earlier occurrence than the sporadic forms. The genes responsible for the familial syndromes are the coding genes for the three sub-units of succinate dehydrogenase (SDHD, SDHB and SDHC) or mitochondrial complex II. Recent discoveries show that these genes are truly implicated in the sporadic forms of the illness and that the research for a germline mutation of a SDH gene is essential for managing patients with paraganglioma and/or pheochromocytoma and their families.
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PMID:[Hereditary paragangliomas and pheochromocytomas]. 1737 14

We report the genetic characteristics of a family with familial paraganglioma syndrome. The index patient was diagnosed with carcinoid tumour of the bronchus at the age of 30 years then later diagnosed with bilateral phaeochromocytoma. His sister had bilateral carotid body tumours. Mutational analyses of succinate dehydrogenase B and SDHD on the index patient showed him to be heterozygous for the M1I mutation of the SDHD gene. A genetic analysis revealed that his sister also had succinate dehydrogenase deficiency with the same mutation. Pre-symptomatic testing confirmed the genetic diagnosis, and led to a clinical diagnosis in an otherwise asymptomatic sibling. Comparison with other known cases of M1I mutation suggests that this is a founder mutation in the Chinese population. Genetic analysis of the succinate dehydrogenase genes can provide a specific diagnosis and allow for genetic screening of at-risk individuals.
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PMID:A Chinese family with familial paraganglioma syndrome due to succinate dehydrogenase deficiency. 1740 45

The mitochondrial succinate dehydrogenase (SDH) is an essential component of the electron transport chain and of the tricarboxylic acid cycle. Also known as complex II, this tetrameric enzyme catalyzes the oxidation of succinate to fumarate and reduces ubiquinone. Mutations in the human SDHB, SDHC, and SDHD genes are tumorigenic, leading to the development of several types of tumors, including paraganglioma and pheochromocytoma. The mechanisms linking SDH mutations to oncogenesis are still unclear. In this work, we used the yeast SDH to investigate the molecular and catalytic effects of tumorigenic or related mutations. We mutated Arg(47) of the Sdh3p subunit to Cys, Glu, and Lys and Asp(88) of the Sdh4p subunit to Asn, Glu, and Lys. Both Arg(47) and Asp(88) are conserved residues, and Arg(47) is a known site of cancer causing mutations in humans. All of the mutants examined have reduced ubiquinone reductase activities. The SDH3 R47K, SDH4 D88E, and SDH4 D88N mutants are sensitive to hyperoxia and paraquat and have elevated rates of superoxide production in vitro and in vivo. We also observed the accumulation and secretion of succinate. Succinate can inhibit prolyl hydroxylase enzymes, which initiate a proliferative response through the activation of hypoxia-inducible factor 1alpha. We suggest that SDH mutations can promote tumor formation by contributing to both reactive oxygen species production and to a proliferative response normally induced by hypoxia via the accumulation of succinate.
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PMID:Ubiquinone-binding site mutations in the Saccharomyces cerevisiae succinate dehydrogenase generate superoxide and lead to the accumulation of succinate. 1763 59

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

The mitochondrial metabolic pathway of the parasitic nematode Ascaris suum changes dramatically during its life cycle, to adapt to changes in the environmental oxygen concentration. We previously showed that A. suum mitochondria express stage-specific isoforms of complex II (succinate-ubiquinone reductase: SQR/quinol-fumarate reductase: QFR). The flavoprotein (Fp) and small subunit of cytochrome b (CybS) in adult complex II differ from those of infective third stage larval (L3) complex II. However, there is no difference in the iron-sulfur cluster (Ip) or the large subunit of cytochrome b (CybL) between adult and L3 isoforms of complex II. In the present study, to clarify the changes that occur in the respiratory chain of A. suum larvae during their migration in the host, we examined enzymatic activity, quinone content and complex II subunit composition in mitochondria of lung stage L3 (LL3) A. suum larvae. LL3 mitochondria showed higher QFR activity ( approximately 160 nmol/min/mg) than mitochondria of A. suum at other stages (L3: approximately 80 nmol/min/mg; adult: approximately 70 nmol/min/mg). Ubiquinone content in LL3 mitochondria was more abundant than rhodoquinone ( approximately 1.8 nmol/mg versus approximately 0.9 nmol/mg). Interestingly, the results of two-dimensional bule-native/sodium dodecyl sulfate polyacrylamide gel electrophoresis analyses showed that LL3 mitochondria contained larval Fp (Fp(L)) and adult Fp (Fp(A)) at a ratio of 1:0.56, and that most LL3 CybS subunits were of the adult form (CybS(A)). This clearly indicates that the rearrangement of complex II begins with a change in the isoform of the anchor CybS subunit, followed by a similar change in the Fp subunit.
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PMID:Change of subunit composition of mitochondrial complex II (succinate-ubiquinone reductase/quinol-fumarate reductase) in Ascaris suum during the migration in the experimental host. 1793 81


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