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)

The pheochromocytomas are an important cause of secondary hypertension. Although pheochromocytoma susceptibility may be associated with germline mutations in the tumor-suppressor genes VHL and NF1 and in the proto-oncogene RET, the genetic basis for most cases of nonsyndromic familial pheochromocytoma is unknown. Recently, pheochromocytoma susceptibility has been associated with germline SDHD mutations. Germline SDHD mutations were originally described in hereditary paraganglioma, a dominantly inherited disorder characterized by vascular tumors in the head and the neck, most frequently at the carotid bifurcation. The gene products of two components of succinate dehydrogenase, SDHC and SDHD, anchor the gene products of two other components, SDHA and SDHB, which form the catalytic core, to the inner-mitochondrial membrane. Although mutations in SDHC and in SDHD may cause hereditary paraganglioma, germline SDHA mutations are associated with juvenile encephalopathy, and the phenotypic consequences of SDHB mutations have not been defined. To investigate the genetic causes of pheochromocytoma, we analyzed SDHB and SDHC, in familial and in sporadic cases. Inactivating SDHB mutations were detected in two of the five kindreds with familial pheochromocytoma, two of the three kindreds with pheochromocytoma and paraganglioma susceptibility, and 1 of the 24 cases of sporadic pheochromocytoma. These findings extend the link between mitochondrial dysfunction and tumorigenesis and suggest that germline SDHB mutations are an important cause of pheochromocytoma susceptibility.
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PMID:Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. 1140 20

Approximately 10% of catecholamine-secreting tumors are malignant, and 10% are familial. These tumors have been associated with several hereditary syndromes, including multiple endocrine neoplasia type 2, von Hippel-Lindau syndrome, neurofibromatosis type 1, and familial paraganglioma. Mutations in succinate dehydrogenase (SDH) subunit genes have been identified in some kindreds with catecholamine-secreting tumors. In 1972 at the Mayo Clinic, a metastatic catecholamine-secreting paraganglioma was diagnosed in a 32-yr-old man. In 1979, 7 yr after the initial surgical treatment, a lytic metastasis to the left femur was found and was treated with local external radiotherapy. Locally metastatic abdominal catecholamine-secreting paragangliomas were diagnosed in the patient's 27-yr-old son. Analyses of the VHL, RET, SDHD, and SDHC genes revealed no mutations. However, a missense point mutation was detected in the SDHB gene: c.725G-->A in exon 7, which alters a conserved arginine at amino acid position 242 to a histidine (R242H). Sequencing of the SDHB gene in the tumors did not reveal any somatic mutations or loss of heterozygosity of the remaining allele. Thirty years after the initial diagnosis, the father is one of the longest living survivors of malignant catecholamine-secreting paraganglioma. Our findings indicate that mutations in SDHB may be associated with metastatic, yet clinically indolent, abdominal paraganglioma in some families.
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PMID:Familial malignant catecholamine-secreting paraganglioma with prolonged survival associated with mutation in the succinate dehydrogenase B gene. 1221 55

We review genetic aspects and recent advances in our understanding of the molecular pathogenesis of familial chromaffin cell tumors (pheochromocytoma, paraganglioma). About 10 percent of pheochromocytomas are familial and occur as part of multiple endocrine neoplasia type 2 (MEN 2), von Hippel-Lindau (VHL) disease, and neurofibromatosis type 1 (NF 1). A subset of paragangliomas, tumors that can also produce and secrete catecholamines, are also familial and occur in patients with germline mutations in genes that encode subunits of the mitochondrial complex II. The precise molecular mechanisms underlying the pathogenesis of chromaffin cell tumors remain widely unknown, although recent studies in hereditary tumors help elucidate their development. In MEN 2, overrepresentation of mutant RET in selected adrenomedullary cells may be an important mechanism in initiating the formation of a pheochromocytoma. In VHL disease, pheochromocytoma development appears to occur according to Knudson's two-hit model, a VHL germline mutation and wildtype allelic deletion. Tumorigenesis of NF1-associated pheochromocytomas remains unknown, as does tumor formation (i.e., carotid body tumor) in patients with germline mutations in SDHB, SDHC, and SDHD, genes that encode subunits of the mitochondrial complex II, the smallest complex in the respiratory chain. Many genetic alterations have been found in sporadic chromaffin cell tumors. However, at present such genetic changes are difficult to place into context with regard to tumor formation and progression.
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PMID:New insights into the genetics of familial chromaffin cell tumors. 1238 38

Phaeochromocytomas arising in adrenal or extra-adrenal sites and paragangliomas of the head and neck, in particular of the carotid bodies, occur sporadically and also in a familial setting. In addition to mutations in RET and VHL in familial disease, germline mutations in SDHD and SDHB genes that encode subunits of mitochondrial complex II have also been associated with the development of familial phaeochromocytomas. To further investigate the role of SDHD and SDHB in the development of these tumours we determined the occurrence of germline SDHD and SDHB mutations in four patients with a family history of phaeochromocytoma with associated head and neck paraganglioma, one patient with a family history of phaeochromocytoma only and two patients with apparently sporadic extra-adrenal phaeochromocytoma, one of whom had early onset disease. Secondly, we investigated whether somatic SDHB mutations correlated with loss of heterozygosity at 1p36 in a subgroup of 11 sporadic and three MEN 2-associated RET-mutation-positive phaeochromocytomas. Novel SDHB mutations were identified in the probands from four families and two apparently sporadic cases (six of seven probands studied), including two missense mutations, a single nonsense and frameshift mutation, as well as two splice site mutations, one of which was shown to have partial penetrance resulting in 'leaky' splicing. Further, five intronic polymorphisms in SDHB were found. No SDHD mutations were identified. In addition, no somatic SDHB mutations were found in the remaining allele of the 11 sporadic adrenal phaeochromocytomas with allelic loss at 1p36 or the three MEN 2-associated RET-mutation-positive phaeochromocytomas. Therefore, we conclude that SDHB has a major role in the pathogenesis of familial phaeochromocytomas, but the possible role of SDHB in sporadic tumours showing allelic loss at 1p36 has yet to be ascertained.
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PMID:Novel succinate dehydrogenase subunit B (SDHB) mutations in familial phaeochromocytomas and paragangliomas, but an absence of somatic SDHB mutations in sporadic phaeochromocytomas. 1261 61

Pheochromocytomas and paragangliomas are tumors of the autonomic nervous system; pheochromocytomas are tumors of the adrenal medulla, and paragangliomas are extra-adrenal tumors arising from either the sympathetic nervous system or parasympathetic ganglia. It has previously been estimated that approximately 10%-15% of pheochromocytomas are due to hereditary causes. However, our increased understanding of the three hereditary syndromes (neurofibromatosis 1, multiple endocrine neoplasia type 2, and von Hippel-Lindau syndrome) in which pheochromocytoma is found and the recent discovery that mutations in genes in the succinate dehydrogenase family (SDHB and SDHD) predispose to pheochromocytoma have necessitated a re-evaluation of the genetic basis of pheochromocytoma. These studies indicate that the frequency of germline mutations associated with isolated pheochromocytoma is higher than previously estimated, with both hospital-based series and a large population-based series indicating that the frequency of germline mutations in RET, VHL, SDHB, and SDHD taken together approximates 20%. In all patients with pheochromocytoma, including those with known hereditary syndrome or a positive family history, the frequency of germline mutations in these four genes together approaches 30%. Given the frequency of germline mutations, consideration should be given to genetic counseling for all patients with pheochromocytoma and is particularly important for individuals with a positive family history, multifocal disease, or a diagnosis before age 50. Identification of patients with hereditary pheochromocytoma is important because it can guide medical management in mutation-positive patients and their families. This review provides an overview of the known genetic syndromes that are commonly associated with pheochromocytoma, examines recent data on the association of germline mutations in the succinate dehydrogenase gene family with pheochromocytoma, and suggests guidelines for the genetic evaluation of pheochromocytoma patients.
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PMID:Pheochromocytoma: the expanding genetic differential diagnosis. 1292 44

Approximately 75% of pheochromocytomas are sporadic. Germline mutations in RET, VHL, SDHB, and SDHD have been shown to cause the 25% that are hereditary. Germline high penetrance gain-of-function RET mutations cause multiple endocrine neoplasia type 2, of which medullary thyroid carcinoma (MTC) and pheochromocytoma are components, whereas loss-of-function mutations cause Hirschprung disease (HSCR). A low-penetrance founder locus, in linkage disequilibrium with a RET ancestral haplotype comprising specific alleles at three intron (IVS) 1 single nucleotide polymorphisms (SNPs) (haplotype 0) and SNP A45A, predisposes to the majority of isolated HSCR. A different low-penetrance locus, in linkage disequilibrium with IVS 1 haplotype 2 and SNP S836S, was associated with a subset of sporadic MTC. We, therefore, sought to determine whether RET might also be a low-penetrance gene for apparently sporadic pheochromocytoma. We analyzed 104 pheochromocytoma cases without germline mutations in RET, VHL, SDHD, and SDHB for their status at A45, S836, three IVS 1 SNPs, and a novel upstream insertion/deletion variant. Pheochromocytoma cases were not associated with either A45A or S836S, but we found that cases were associated with haplotype 0 (P = 0.032). However, unlike HSCR, this pheochromocytoma-associated haplotype 0 was not associated with A45A. Taken together with the strengthening of association with the addition of the 5' insertion/deletion variant data (P = 0.016), our observations suggest the presence of a low-penetrance pheochromocytoma susceptibility locus in a region upstream of the putative loci for HSCR and apparently sporadic MTC.
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PMID:Intronic single nucleotide polymorphisms in the RET protooncogene are associated with a subset of apparently sporadic pheochromocytoma and may modulate age of onset. 1455 73

Until very recently, the majority of hereditary pheochromocytomas were related to the MEN 2 and the VHL. In rare instances, hereditary pheochromocytoma was reported in patients with NF1. In addition, nonsyndromic hereditary pheochromocytomas have been reported. Recently, three more genes (SDHD, SDHB, and SDHC) which are all related subunits of the mitochondrial complex II have been identified to cause susceptibility to pheochromocytoma and/or paraganglioma. Hence, mutation analysis of VHL, RET, SDHB, and SDHD is generally recommended in patients with pheochromocytoma regardless of their family history or other features suggestive for a hereditary form. Mutation analysis should start with VHL and RET. However, in the presence of extra-adrenal pheochromocytoma, it may be more useful to screen for VHL, SDHD and SDHB mutations. It is of interest that various different genes can lead to one type of tumor formation. A common pathway (i.e. oxygen sensing) has been shown for VHL and SDHX. However, although several genes that are involved in the pathogenesis of hereditary pheochromocytoma are known, the precise molecular steps in tumorigenesis are widely unknown. In addition, recent data in MEN 2 pheochromocytomas point to a 'second hit' mechanism as a trigger for tumor formation. The molecular pathogenesis of sporadic pheochromocytomas remains obscure [114].
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PMID:The genetic basis of pheochromocytoma. 1467 4

More than 30% of adrenal pheochromocytomas are hereditary. These neuroendocrine tumors are major components of three inherited cancer syndromes: multiple endocrine neoplasia type 2, von Hippel-Lindau disease (VHL), and pheochromocytoma/paraganglioma syndrome (PC/PGL). Germline mutations in RET; VHL; and SDHB, SDHC, and SDHD are associated with multiple endocrine neoplasia type 2, VHL, and PC/PGL, respectively. The majority (>70%) of hereditary extraadrenal PCs [catecholamine-secreting paragangliomas (PGL)] are accounted for by germline intragenic mutations in SDHB, SDHC, or SDHD. Therefore, a subset of hereditary PGL is not accounted for. Here we report two unrelated hereditary PGL families, one with a germline whole-gene deletion of SDHD (family 4194), the other a partial deletion of SDHB (family BRZ01). Although they were initially designated mutation negative for all of the PC-associated genes after PCR-based analysis, we suspected that a large deletion or rearrangement might be present. Genotyping around the PC-associated genes demonstrated that both families were consistent with linkage with one of these genes. Using fine structure genotyping and semiquantitative duplex PCR analysis, we identified an approximately 96-kb deletion spanning SDHD in family 4194 and an approximately 1-kb deletion involving the 5' end of SDHB in family BRZ01. Thus, including SDHB and SDHD deletion analysis could increase gene-testing sensitivity for PGL patients, which would aid in genetic counseling and management of patients and families.
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PMID:Large germline deletions of mitochondrial complex II subunits SDHB and SDHD in hereditary paraganglioma. 1553 30

Pheochromocytomas and abdominal paragangliomas are catecholamine-producing tumors of the sympathetic nervous system, while head and neck paragangliomas are non-secreting tumors of parasympathetic origin. Recent developments in clinical and molecular research on these tumor forms have significantly clarified their genetic backgrounds and challenged the view of "pheochromocytoma as the 10% rule tumor." Firstly, a larger proportion of these tumors are today discovered in normotensive patients during imaging carried out for other reasons than suspicion of pheochromocytoma. Secondly, although the differential diagnosis between malignant and benign tumors remains a challenge, the risk of malignancy well exceeds the classical 10% in patients with extra-adrenal disease, and/or carriers of germ-line SDHB mutations. Finally, up to a third of patients carry a germ-line mutation in a gene predisposing to pheochromocytoma and/or paraganglioma. Identification of a constitutional mutation in RET, VHL, SDHD, or SDHB has implications for clinical screening and follow-up for both the patient and for relatives at risk who can be identified by screening for the same mutation. Genetic testing in apparently sporadic cases is therefore regarded as beneficial, especially in patients diagnosed before 50 years of age, and in patients with bilateral, multifocal, malignant and/or extra-adrenal disease.
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PMID:Pheochromocytoma and functional paraganglioma syndrome: no longer the 10% tumor. 1571 71

Pheochromocytoma and paraganglioma are tumors of the autonomous nervous system mainly occurring in the adrenal medulla, but also in the extraadrenal paraganglias of the abdomen, thorax, neck and skull basis. The etiology comprises germline mutations of now 6 genes. About 10 years known are the RET gene susceptible for multiple endocrine neoplasia type 2, the VHL gene for von Hippel-Lindau Disease, and the NF 1 gene for neurofibromatosis Recklinghausen (neuro- fibromatosis type 1). Since 2000 the genes for succinatedehydrogenase subunits SDHB, SDHC, and SDHD have been identified for paraganglioma syndromes type 4, type 3, and type 1 respectively. Investigations of series of pheochromocytoma patients identified germline mutations in one of the genes SDHB, SDHD, VHL and RET in 24% to 50% of the patients. Multifocal tumors, young age and positive family history, known features associated with inheritence, have not been present in all patients. Therefore, analyses of blood DNA for mutations in these genes are recommended. Positive tests provide the patients and their relatives with essential platforms for clinical care. Experiences in this field of medicine have shown that optimal management of patients with pheochromocytoma-associated syndromes is a high challenge. National registries may be instrumental in order to provide with adequate facilities.
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PMID:New genetic causes of pheochromocytoma: current concepts and the clinical relevance. 1583 76


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