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

---

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.
...
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.
...
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.
...
PMID:New insights into the genetics of familial chromaffin cell tumors. 1238 38

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].
...
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.
...
PMID:Large germline deletions of mitochondrial complex II subunits SDHB and SDHD in hereditary paraganglioma. 1553 30

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.
...
PMID:New genetic causes of pheochromocytoma: current concepts and the clinical relevance. 1583 76

Pheochromocytoma are tumors derived from chromaffin cells that secrete catecholamines. These catecholamines may lead to increased blood pressure and even death. Historically, pheochromocytoma have been described as 10 tumor, i.e. about 10 were believed to be malignant, 10 were found to be extra-adrenal, and 10 were meant to be bilateral. Also, about 10 were considered to be hereditary. In these instances, they were most often part of either the multiple endocrine neoplasia type 2 (MEN 2) syndrome or the von Hippel-Lindau (VHL) disease. The genes (RET and VHL) involved have been known for several years and their function is the subject of ongoing investigation. Very recently, several genes (SDHD, SDHB, and SDHC) that belong to the mitochondrial complex II have been identified to be involved in the so-called pheochromocytoma-paraganglioma syndrome. Only SDHD and SDHB have so far been implicated in the pathogenesis of pheochromocytoma.
...
PMID:Pheochromocytoma-associated syndromes: genes, proteins and functions of RET, VHL and SDHx. 1588 6

Recent advances in the molecular genetic of adrenal tumors give new insights in the pathophysiology of these neoplasms in both hereditary and sporadic cases. The practice of genetic counselling in patients with adrenal tumors have been recently changed by the identification and the understanding of new specific hereditary cancer susceptibility syndromes. In the case of sporadic adrenocortical tumors these progress also offer new prognosis predictors. The genetic predisposition to adrenocortical cancer in children has been well established in the Li-Fraumeni and Beckewith-Wiedeman syndromes due to germline p53 mutation located at 17p13 and dysregulation of the imprinted IGF-2 locus at 11p15, respectively. Adrenocortical tumors are also observed in Multiple Endocrine Neoplasia type I syndrome. Cushing's syndrome due to primary pigmented nodular adrenocortical disease have been observed in patients with germline PRKAR1A inactivating mutations. Interestingly allelic loss at 17p13 and 11p15 have been observed in sporadic adrenocortical cancer and somatic PRKAR1A mutations in secreting adrenocortical adenomas. The potential interest of these finding for the diagnosis of these tumors will be discussed. In the case of pheochromocytoma and paraganglioma, the demonstration that three genes encoding three succinate dehydrogenase subunits (SDHD, SDHB, SDHC), belonging to the complex II of the respiratory chain in the mitochondria, are involved in the genetics of familial and especially in apparently sporadic phaeochromocytomas have dramatically modified our practice. Up to date, four diagnosis of familal disease (multiple endocrine neoplasia type II, von Hippel Lindau disease, neurofibromatosis type 1 and hereditary paraganglioma) should be discussed and causative mutations in six different phaechomocytoma susceptibility genes (RET, VHL, NF1, SDHB, SDHD, SDHC) could be identified. In this review, we will perform an update compiling these new clinical, genetic and functional data recently published. We will suggest guidelines for the practice of the phaeochomocytoma genetic testing in the patients and their families, and for an early detection of tumors in the patients or in individuals determined to be at-risk of disease by the presymptomatic genetic testing.
...
PMID:New insights in the genetics of adrenocortical tumors, pheochromocytomas and paragangliomas. 1600 32

Mutations in VHL, RET, NF1, SDHB, SDHC, and SDHD can give rise to pheochromocytoma/paraganglioma. These different genetic lesions may all act by decreasing the activity of a 2-oxoglutarate-dependent oxygenase, SM-20/EglN3/PHD3, resulting in reduced apoptosis of neural crest cells during development.
...
PMID:A common pathway for genetic events leading to pheochromocytoma. 1609 68

Pheochromocytoma and paraganglioma are rare neuroendocrine tumors that arise in the adrenal medulla and the extra-adrenal paraganglia, respectively. Inheritance of these tumors is mainly a result of mutations affecting the VHL, RET, NF1, and SDH genes. Germ-line mutations of the SDH genes have been found to account for nearly 10% of apparently sporadic cases. Nevertheless, alterations other than point mutations have not yet been well characterized. In this study, we investigated the frequency of gross SDH deletions in 24 patients who tested negative for point mutations and had at least one of the recommended features for genetic testing. For this purpose, we used a technique that is easy to implement in the lab to specifically detect gross deletions affecting SDHB, SDHC, and SDHD. We identified 3 heterozygous SDHB deletions (3/24) in 3 independent cases with paraganglioma: 1 whole SDHB deletion and 2 deletions exclusively affecting exon 1. These latter mutations match the unique gross deletion previously reported, indicating this region could be a hot spot for gross SDHB deletions. It seems likely that these alterations can account for a considerable number of both familial and apparently sporadic paraganglioma cases. Although this is the first report describing the presence of gross deletions in patients with apparently sporadic paragangliomas, the extra-adrenal location of the tumor seems to constitute a determining factor for whether to include these patients in genetic testing for gross deletions in the SDHB gene.
...
PMID:Gross SDHB deletions in patients with paraganglioma detected by multiplex PCR: a possible hot spot? 1625 55


1 2 3 4 5 6 7 8 9 Next >>

---