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)

Paragangliomas (PGLs) derive from either sympathetic chromaffin tissue in adrenal and extra-adrenal abdominal or thoracic locations, or from parasympathetic tissue of the head and neck. Mutations of nuclear genes encoding subunits B, C, and D of the mitochondrial enzyme succinate dehydrogenase (SDHB 1p35-p36.1, SDHC 1q21, SDHD 11q23) give rise to hereditary PGL syndromes PGL4, PGL3, and PGL1 respectively. The susceptibility gene for PGL2 on 11q13.1 remains unidentified. Mitochondrial dysfunction due to SDHx mutations have been linked to tumorigenesis by upregulation of hypoxic and angiogenesis pathways, apoptosis resistance and developmental culling of neuronal precursor cells. SDHB-, SDHC-, and SDHD-associated PGLs give rise to more or less distinct clinical phenotypes. SDHB mutations mainly predispose to extra-adrenal, and to a lesser extent, adrenal PGLs, with a high malignant potential, but also head and neck paragangliomas (HNPGL). SDHD mutations are typically associated with multifocal HNPGL and usually benign adrenal and extra-adrenal PGLs. SDHC mutations are a rare cause of mainly HNPGL. Most abdominal and thoracic SDHB-PGLs hypersecrete either norepinephrine or norepinephrine and dopamine. However, only some hypersecrete dopamine, are biochemically silent. The biochemical phenotype of SDHD-PGL has not been systematically studied. For the localization of PGL, several positron emission tomography (PET) tracers are available. Metastatic SDHB-PGL is the best localized by [(18)F]-fluorodeoxyglucose PET. The identification of SDHx mutations in patients with PGL is warranted for a tailor-made approach to the biochemical diagnosis, imaging, treatment, follow-up, and family screening.
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PMID:Clinical aspects of SDHx-related pheochromocytoma and paraganglioma. 1919 77

The mitochondrial succinate dehydrogenase (SDH) is an iron-sulfur flavoenzyme linking the Krebs cycle and the mitochondrial respiratory chain. Mutations in the human SDHB, SDHC and SDHD genes are responsible for the development of paraganglioma and pheochromocytoma, tumors of the head and neck or the adrenal medulla, respectively. In recent years, SDH has become recognized as a source of reactive oxygen species, which may contribute to tumorigenesis. We have developed a Caenorhabditis elegans model to investigate the molecular and catalytic effects of mutations in the sdhb-1 gene, which encodes the SDH iron-sulfur subunit. We created mutations in Pro211; this residue is located near the site of ubiquinone reduction and is conserved in human SDHB (Pro197), where it is associated with tumorigenesis. Mutant phenotypes ranged from relatively benign to lethal and were characterized by hypersensitivity to oxidative stress, a shortened life span, impaired respiration and overproduction of superoxide. Our data suggest that the SDH ubiquinone-binding site can become a source of superoxide and that the pathological consequences of SDH mutations can be mitigated with antioxidants, such as ascorbate and N-acetyl-l-cysteine. Our work leads to a better understanding of the relationship between genotype and phenotype in respiratory chain mutations and of the mechanisms of aging and tumorigenesis.
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PMID:Mutations in the C. elegans succinate dehydrogenase iron-sulfur subunit promote superoxide generation and premature aging. 1923 6

Familial paragangliomas/pheochromocytomas are dominantly inherited disorders characterized by the development of highly vascularized tumors of the head and neck, derived from non-chromaffin cells of the extra-adrenal paraganglia, and tumors with endocrine activity, derived from chromaffin cells, usually located in the adrenal medulla and pre- and para-vertebral thoracoabdominal regions. Germline inactivating heterozygous mutations in one of the genes encoding for succinate dehydrogenase subunits B, C or D (SDHB, SDHC or SDHD) are responsible for hereditary paragangliomas (PGLs), accounting for nearly 70% of familial cases. Particularly in the SDHD gene, different types of mutations have been found, nevertheless, alterations other than point mutations and deletion leading to missense/nonsense/splicing mutations are extremely rare. Here we report a family with multiple cases of PGL which co-segregates with a novel SDHD gene mutation predictable to give rise to an abnormal gene product (CybS). The identification of the molecular event responsible for PGL in our family made genetic counseling particularly useful for younger first degree relatives at risk to develop this late-onset disease.
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PMID:A novel mutation in the SDHD gene responsible for familial paraganglioma. Medical and psychological implications. 1923 85

Paragangliomas and pheochromocytomas are neuroendocrine tumors arising in the extraadrenal and adrenal medulla, respectively. These tumors appear in certain familial syndromes, such as multiple endocrine neoplasia types 1 and 2, Von Hippel Lindau disease, neurofibromatosis type 1 and familial paraganglioma syndromes. The latter syndromes show a strong association with germline mutations of succinate dehydrogenase subunits, such as SDHB, SDHC and SDHD. This enzyme complex is related to tumorigenesis through mechanisms involved in cell proliferation, apoptosis, and alterations in oxygen sensing function, although none of these factors has been clearly identified as a cause of tumoral development. In the last few years, several studies have been performed of these genes in relation to correct diagnosis of paraganglioma and pheochromocytoma, as well as determination of germline mutations in familial and sporadic cases and its utility in genetic counselling in these patients.
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PMID:[Genetic and molecular bases of paragangliomas]. 1924 72

Pheochromocytomas and Paragangliomas (PGL) form the group of paraganglial tumours which can occur in any paraganglia from the skull base to the pelvic floor. The terminology is not uniform. While the World Health Organization (WHO) applies pheochromocytoma exclusively to adrenal tumours, many clinicians use the term pheochromocytoma also for extra-adrenal abdominal and thoracic tumours, since by tradition pheochromocytoma is a vasoactive tumour. In contrast, head and neck paraganglioma is mostly only a space-occupying mass. The diagnosis is confirmed by both biochemical testing and radiological imaging. One third of patients with pheochromocytomas and paragangliomas are carriers of germline mutations in one of 6 genes and thus have a hereditary disorder. About 1% of Neurofibromatosis (NF) 1 patients have pheochromocytomas. All pheochromocytoma patients with NF 1 also show cutaneous lesions. About 50% of MEN2 patients harbour pheochromocytoma. The dominant lesion in this entity is Medullary Thyroid Carcinoma (MTC) occurring in up to 100% of patients. Von Hippel-Lindau disease (VHL)is found in about 20% of patients in association with pheochromocytoma. VHL is classified as type 1 predominantly without and type 2 predominantly with pheochromocytoma. Other important components of VHL are hemangioblastomas of the eye and Central Nervous System (CNS), renal clear cell carcinoma, multiple pancreatic cysts and islet cell carcinoma. PGL syndromes have been genetically characterized as PGL 1, 3 and 4 and are caused by mutations in the succinate dehydrogenase (SDH) subunit D, C and B genes, respectively (SDHD, SDHC and SDHB). Paraganglioma syndromes include predisposition to paraganglial tumours in any location, whereas PGL 3 patients mostly show only head and neck paragangliomas. All syndromes associated with paraganglial tumours are autosomal dominantly transmitted, but patients with SDHD mutations develop tumours only if they inherit the mutation from the father. Familial paraganglial tumours are characterized by younger age at diagnosis and more frequently multifocal and extra-adrenal abdominal pheochromocytomas. Patients with PGL 4 and less frequently VHL, are particularly predisposed to malignant pheochromocytoma. Endoscopic surgery is the primary treatment for pheochromocytoma. For malignant cases, chemotherapeutic as well as radionuclear approaches are available. No specific treatment has been proposed for prevention of the disease in inherited disorders. Thus, early diagnosis and regular follow-up are the only means for a better outcome.
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PMID:Familial pheochromocytoma. 1926 19

Respiratory chain complex II has been extensively studied but little is known about its assembly and the role of its heme group. Mutations in the phylogenetically conserved histidine 127 of the SDHC subunit have been shown to abrogate heme binding in yeast and bacteria without impairing complex II assembly or enzymatic activities. Here we show that in mammalian cells these mutations lead to a complete reduction of SDHC in mitochondria, a destabilisation of SDHD and SDHB, and to an abrogation of complex II enzymatic activities, suggesting that in mammalian cells complex II assembly is more complex than in lower organisms.
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PMID:Mutations in the heme b-binding residue of SDHC inhibit assembly of respiratory chain complex II in mammalian cells. 1933 49

Multiple genes and their variants that lend susceptibility to many diseases will play a major role in clinical routine. Genetics-based cost reduction strategies in diagnostic processes are important in the setting of multiple susceptibility genes for a single disease. Head and neck paraganglioma (HNP) is caused by germline mutations of at least three succinate dehydrogenase subunit genes (SDHx). Mutation analysis for all 3 costs approximately US$2,700 per patient. Genetic classification is essential for downstream management of the patient and preemptive management of family members. Utilizing HNP as a model, we wanted to determine predictors to prioritize the most heritable clinical presentations and which gene to begin testing in HNP presentations, to reduce costs of genetic screening. Patients were tested for SDHB, SDHC, and SDHD intragenic mutations and large deletions. Clinical parameters were analyzed as potential predictors for finding germline mutations. Cost reduction was calculated between prioritized gene testing compared with that for all genes. Of 598 patients, 30.6% had SDHx germline mutations: 34.4% in SDHB, 14.2% SDHC, and 51.4% SDHD. Predictors for an SDHx mutation are family history [odds ratio (OR), 37.9], previous pheochromocytoma (OR, 10.9), multiple HNP (OR, 10.6), age <or=40 years (OR, 4.0), and male gender (OR, 3.5). By screening only preselected cases and a stepwise approach, 60% cost reduction can be achieved, with 91.8% sensitivity and 94.5% negative predictive value. Our data give evidence that clinical parameters can predict for mutation and help prioritize gene testing to reduce costs in HNP. Such strategy is cost-saving in the practice of genetics-based personalized health care.
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PMID:Clinical predictors for germline mutations in head and neck paraganglioma patients: cost reduction strategy in genetic diagnostic process as fall-out. 1935 33

In the last few years several papers have reported on the association between mutations of the genes encoding the structural (SDHC, SDHD) and catalytic (SDHB) subunits of succinate dehydrogenase and the occurrence of hereditary pheochromocytomas/paragangliomas (Pheo/PGL) syndromes. We diagnosed a malignant extraadrenal Pheo in a 38-yr-old man with abdominal lesions; many areas of increased uptake at octreoscan scintigraphy in the skeleton indicated metastatic disease. We then approached genetic analysis through the screening of the SDHB, SDHC, and SDHD genes. Here we report a heterozygous G>A transversion at position +1 of intron 4 of SDHB gene. To clarify this mutation we performed cDNA analysis by RT-PCR and we assume that the splice site mutation in intron 4 abolishes the consensus splice donor sequence leading to an in-frame deletion of 18 amino acid. This finding indicates once again that SDHB mutations could predispose to malignant Pheo.
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PMID:Malignant extra-adrenal pheochromocytoma caused by an SDHB intronic variation leading to a 54-bp deletion in exon 4. 1941 6

The carotid body (CB) is a highly specialized small organ located at the bifurcation of the common carotid artery in the neck and plays an important role in acute adaptation to hypoxia, which is the most common tumor site in head and neck paragangliomas. Although carotid body tumors (CBTs) are mostly slow-growing and benign, they can cause significant morbidity because of their proximity to major arteries and nerves in the head and neck. CBTs can be caused by a genetic predisposition and by chronic hypoxic stimulation. Currently, inactivating germline mutations in the mitochondrial complex II subunits SDHB, SDHC, and SDHD have been identified as genetic risk factors for CB tumors (CBTs). Another locus at chromosome 11q13, identified by linkage analysis in a single family, may harbor a fourth susceptibility gene. This paper highlights the recent research advances in etiologic mechanism of molecular biological aspect of CBT.
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PMID:[Research advances in molecular biology of carotid body tumor]. 1941 4

Carney triad (CT) describes the association of paragangliomas (PGLs) with gastrointestinal stromal tumours (GISTs) and pulmonary chondromas (PCH). A number of other lesions have been described in the condition including pheochromocytomas, oesophageal leiomyomas and adrenocortical adenomas; CT is a novel form of multiple endocrine neoplasia (MEN), a genetic condition with a female predilection. Inactivating mutations of the mitochondrial complex II succinate dehydrogenase (SDH) enzyme subunits SDHB, SDHC and SDHD have been found in familial and sporadic PGLs, and gain-of-function mutations of the oncogenes c-kit (KIT) and platelet-derived growth factor receptor A (PDGFRA) cause sporadic and familial GISTs. We recently reported an international series of patients with CT, 34 females and three males (median age of presentation 21 years) who did not carry SDHA, SDHB, SDHC, SDHD, KIT or PDGFRA gene mutations. Comparative genomic hybridization revealed a number of DNA copy number changes. The most frequent and greatest contiguous change was a deletion within the 1pcen13-q21 region, which harbours the SDHC gene. Another frequent change was loss of 1p. Although GISTs showed more frequent losses of 1p than PGLs, the pattern of chromosomal changes was similar in the two tumours despite their different tissue origin and histology; the findings were consistent with a common genetic aetiology of these two tumours in CT. In a separate condition, in which the association (or dyad) of GISTs with PGLs is inherited in an autosomal dominant manner (Carney-Stratakis syndrome, CSS), germline mutations of the SDHB, SDHC and SDHD genes (but not KIT or PDFGRA) were found; GISTs in this condition were caused by SDH deficiency. We conclude that CT is a novel MEN syndrome whose genetic defect remains elusive. CSS is caused by SDH defects, suggesting that sarcomas (GISTs) can be caused by defective mitochondrial oxidation, consistent with recent data implicating this enzyme in a variety of endocrine and other tumours. The above have clinical implications (i) for patients with GISTs that are cKIT- and PDGFRA-mutation negative: these tumours are usually resistant to treatment with currently available tyrosine kinase inhibitors and may be part of a syndrome such as CT or CSS; and (ii) for patients with an inherited PGL syndrome, family history should be explored to identify any other tumours in the family, and in particular other endocrine lesions and GISTs.
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PMID:The triad of paragangliomas, gastric stromal tumours and pulmonary chondromas (Carney triad), and the dyad of paragangliomas and gastric stromal sarcomas (Carney-Stratakis syndrome): molecular genetics and clinical implications. 1952 24


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