Login to MyKarger

New to MyKarger? Click here to sign up.



Login with Facebook

Forgot your password?

Authors, Editors, Reviewers

For Manuscript Submission, Check or Review Login please go to Submission Websites List.

Submission Websites List

Institutional Login
(Shibboleth or Open Athens)

For the academic login, please select your country in the dropdown list. You will be redirected to verify your credentials.

Mini Review

Free Access

Hereditary Paraganglioma/Pheochromocytoma and Inherited Succinate Dehydrogenase Deficiency

Favier J.a · Brière J.-J.b · Strompf L.a · Amar L.a · Filali M.a · Jeunemaitre X.a · Rustin P.b · Gimenez-Roqueplo A.-P.a

Author affiliations

aDépartement de Génétique, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Université Paris V and INSERM U36, Collège de France, and bINSERM U676, Hôpital Robert Debré, Paris, France

Corresponding Author

Dr. Anne-Paule Gimenez-Roqueplo

Département de Génétique, Hôpital Européen Georges Pompidou

20–40, rue Leblanc, FR–75015 Paris (France)

Tel. +33 1 5609 3881, Fax +33 1 5609 3884

E-Mail anne-paule.gimenez@hop.egp.ap-hop-paris.fr

Related Articles for ""

Horm Res 2005;63:171–179

Abstract

Mitochondrial complex II, or succinate dehydrogenase, is a key enzymatic complex involved in both the tricarboxylic acid (TCA) cycle and oxidative phosphorylation as part of the mitochondrial respiratory chain. Germline succinate dehydrogenase subunit A (SDHA) mutations have been reported in a few patients with a classical mitochondrial neurodegenerative disease. Mutations in the genes encoding the three other succinate dehydrogenase subunits (SDHB, SDHC and SDHD) have been identified in patients affected by familial or ‘apparently sporadic’ paraganglioma and/or pheochromocytoma, an autosomal inherited cancer-susceptibility syndrome. These discoveries have dramatically changed the work-up and genetic counseling of patients and families with paragangliomas and/or pheochromocytomas. The subsequent identification of germline mutations in the gene encoding fumarase – another TCA cycle enzyme – in a new hereditary form of susceptibility to renal, uterine and cutaneous tumors has highlighted the potential role of the TCA cycle and, more generally, of the mitochondria in cancer.

© 2005 S. Karger AG, Basel


Keywords

Paraganglioma · Pheochromocytoma · Mitochondria · Cancer genetics · SDHA · SDHB · SDHC · SDHD ·


Introduction

Mitochondrial diseases result in a number of clinical presentations, ranging from organ-specific involvement to multisystemic disorders, often with prominent neurological features [1]. The recent discovery of germline mutations in the SDH genes encoding succinate dehydrogenase in patients with familial paraganglioma (PGL) or pheochromocytoma (PHEO) has revealed an unexpected and primary role of mitochondrial deficiency in carcinogenesis [2]. SDH gene mutations are also frequently encountered in patients with an apparently sporadic form of PGL or PHEO. Further evidence that mitochondria play a role in carcinogenesis has been provided by the identification of mutations affecting the fumarate hydratase (FH) gene [3]. This review focuses on the recently established link between mitochondrial dysfunction and tumorigenesis. The consequences of these new findings for the diagnosis, treatment and follow-up of patients with PHEO and PGL will be discussed in detail.

Mitochondrial Complex II or Succinate Dehydrogenase

Description

Most of the energy used by the cell is generated by mitochondrial oxidative phosphorylation, via the respiratory chain, which produces ATP from the energy released by substrate oxidation. The metabolic pathways responsible for substrate oxidation depend on the tissues and cells concerned, but occur in the mitochondrial matrix. The tricarboxylic acid (TCA) cycle, β-oxidation of fatty acids, and many other enzymatic reactions integrate mitochondrial matrix metabolism into the general metabolic network of the cell. Indeed, as many as a thousand nuclear genes are thought to encode the components of the mitochondrial metabolic machinery. The oxidation of organic acids via the TCA cycle produces the reduced equivalents – NADH and FADH2 – required for the production of most of the cell’s ATP via the respiratory chain. Oxidative phosphorylation couples ATP synthesis to the flow of electrons from NADH or FADH2 to O2, thanks to the proton gradient setup by electron transfer through the respiratory chain complexes of the inner mitochondrial membrane. With only four subunits, mitochondrial complex II (succinate:ubiquinone oxidoreductase, SQR, EC 1.3.5.1) is the smallest complex in the respiratory chain. It is located at the crossroads between the respiratory chain and the TCA cycle. Together with a number of inner membrane-bound dehydrogenases, it feeds electrons to the quinone pool, reducing ubiquinone (Q) to ubiquinol (QH2). The specific redox properties of this complex suggest that it is a key enzyme in control of the redox status of the Q pool, and therefore in the regulation of oxidative stress [4]. In the TCA cycle, it catalyzes the oxidation of succinate to fumarate (fig. 1). The complex comprises four subunits: SDHA, SDHB, SDHC and SDHD. The hydrophilic, catalytic part of the complex consists of a 70-kDa flavoprotein (Fp, SDHA) and a 30-kDa iron-sulfur protein (Ip, SDHB), which form the succinate dehydrogenase (SDH) enzyme. The hydrophobic part of the complex consists of the 15-kDa (SDHC) and 12.5-kDa (SDHD) subunits, which anchor the complex in the inner mitochondrial membrane and are necessary for electron transfer to the Q pool.

Fig. 1

The key role of mitochondrial complex II. Complex II connects the respiratory chain in the inner mitochondrial membrane with the tricarboxylic acid (TCA) cycle in the matrix. In the respiratory chain, complexes I and II reduce ubiquinone (Q) to ubiquinol (QH2). In the TCA cycle, succinate is oxidized by succinate dehydrogenase to generate fumarate. The enzymes involved in this process are: (1) fumarase, (2) malate dehydrogenase, (3) aspartate aminotransferase, (4) α-ketoglutarate dehydrogenase, (5) succinyl CoA synthetase, (6) pyruvate dehydrogenase, (7) citrate synthetase, (8) aconitase, and (9) isocitrate dehydrogenase.

http://www.karger.com/WebMaterial/ShowPic/314430

The succinate binding site of the enzyme is located on the Fp subunit, to which a flavin adenine dinucleotide (FAD) binds covalently. Electrons derived from the oxidation of succinate are transferred to the flavin moiety (FADH2) and then on to the three iron-sulfur clusters – [2Fe-2S], [4Fe-4S], [3Fe-4S] – of the Ip subunit. They are then transferred to the Q pool via the anchorage domain of complex II, which contains a b-type cytochrome and Q binding sites [5]. The three-dimensional structure of Escherichia coli SDH was recently elucidated and shows that SQR plays a role in preventing the formation of reactive oxygen species (ROS) [6].

The SDH Genes

The four-subunit complex II is the only respiratory chain complex exclusively encoded by nuclear genes – SDHA (15 exons, 664 amino acids) [7], SDHB (8 exons, 281 amino acids) [8, 9], SDHC (6 exons, 170 amino acids) [10], and SDHD (4 exons, 160 amino acids) [10] – located on four different chromosome regions: 5p15, 1p35–36.1, 1q21 and 11q23, respectively. Two forms of SDHA have been described in humans, and are expressed differentially according to the cell type [11]. A point mutation in the SDHC gene of Caenorhabditis elegans, giving rise to the mev-1 mutant, causes premature aging and oxidative stress by increasing ROS production [12]. In humans, mutations in SDH genes have been shown to cause two very different types of disease. Mutations in SDHA cause a neurological disease, with an early onset and brain lesions typical of Leigh syndrome. Mutations in SDHB, SDHC and SDHD predispose the individual to a particular type of cancer: hereditary PGL/PHEO.

SDHA Mutations Cause Leigh Syndrome

Only five different germline mutations have been described in SDHA, which is located on chromosome 5 (table 1). The first one (R554W) was identified in one consanguineous family. The patients, homozygous for the mutation, presented early-onset neurodegenerative disease with Leigh syndrome (MIM 256000), due to a severe complex II deficiency. The expression of this mutation in yeast resulted in a 50% decrease in SDH activity [13]. A similar phenotype was described in a compound heterozygous patient with a paternally inherited A524V mutation and a maternally inherited M1L mutation [14]. Another homozygous mutation (G555D) was identified in a child with complex II deficiency, who died at 5.5 months of age following a respiratory infection [15]. Finally, a heterozygous base change (R408C) was reported in 2 sisters with a partial complex II deficiency (residual activity >50%) and caused a milder phenotype associating optic atrophy, ataxia and myopathy [16]. Leigh syndrome and the various neuromuscular symptoms observed in this small number of patients with mutations in the SDHA gene are features frequently observed in patients with respiratory chain deficiency [17].

Table 1

Mutations in SDHA gene

http://www.karger.com/WebMaterial/ShowPic/314432

Hereditary Paraganglioma and Pheochromocytoma: SDHD, SDHB, SDHC Deficiencies

Clinical Presentation of Paraganglioma and Pheochromocytoma

PGLs are neuroendocrine tumors that may secrete catecholamines. They occur most frequently in the head (glomus tympanicum and jugulare), neck (carotid body and glomus vagale), adrenal medulla and extra-adrenal sympathetic ganglia. The paraganglia and other elements of the autonomic nervous system arise from neural crest cells, as the thyroid C-cells, and are distributed from the base of the skull to the pelvic floor. During embryogenesis, neural crest cells migrate from the neural tube to form the parasympathetic system in the head and neck, the sympathetic nervous system in the thoracic and abdominal region and the adrenal medulla (fig. 2). PGLs may occur at any location in this migration process. PGLs arising from the parasympathetic system (carotid body, glomus vagal, glomus jugulare and tympanicum) usually have no endocrine activity. However, PGLs arising from the adrenomedulla or sympathetic ganglia (organ of Zuckerkandl or periaortic region, perirenal region, bladder, mediastinum, etc.) may be functional and secrete catecholamines. According to current nomenclature, the term ‘pheochromocytoma’ corresponds to a secreting PGL evolving from the adrenal medulla, whereas a ‘functional PGL’ refers to an extra-adrenal secreting PGL, which was previously known as an ‘ectopic PHEO’. The tumors now described as ‘carotid body PGL’ were formerly known as ‘chemodectoma’ due to the chemoreceptor function of the carotid body.

Fig. 2

Neural crest cell migration. Schematic representation of the migration of neural crest cells in the fifth week of development, in a transverse section of a human embryo. The parasympathetic ganglia in the head and neck, the sympathetic thoracic and abdominal ganglia, the organ of Zuckerkandl at the aortic bifurcation and the adrenal medulla develop from these cells.

http://www.karger.com/WebMaterial/ShowPic/314429

PGLs are generally benign, highly vascularized tumors occurring close to the major blood vessels and cranial nerves. About 10% of these tumors are malignant. PGLs are usually diagnosed on the basis of the presence of a mass in the neck, pulsatile tinnitus or hearing loss. A head and neck MRI or CT scan can be used to characterize the tumor in terms of vascularization, as well as location and extent of the tumor [18]. The only curative therapy is early surgical resection of the tumor. Before commencing surgery, other sites of PGL or PHEO should be sought by determining 24-hour urinary or plasma metanephrine concentration and radiological methods such as 123I-metaiodobenzylguanidine (mIBG) scintigraphy and/or octreotide scintigraphy and/or 18F-DOPA or 18F-fluorodopamine whole-body positron emission tomography (PET). Finally, angiography is worthwhile to assess the extent of the tumor and for presurgical embolization [19]. In cases of PHEO, surgery must be accompanied by preparatory drug treatment and the assistance of a specialized team of anesthetists [20]. Radiation therapy may also be proposed for large, rapidly growing tumors.

Hereditary Paraganglioma

The existence of familial forms of PGL has been suspected since the 1940s, with reports of several cases of head and neck PGL in the same family. PGLs seem to be inherited in about 30% of cases. The hereditary form of PGL is usually characterized by an early onset and a more severe presentation than the sporadic form. These tumors often display bilateral and multiple locations and may be recurrent or malignant. The presence of one or several secreting tumors is not rare and contributes to the severity of inherited PGL [21]. Such PGLs constitute a genetically heterogeneous group of diseases as four different loci have been implicated: PGL1 on 11q23, PGL2 on 11q13, PGL3 on 1q21 and PGL4 on 1p36.This condition is subject to autosomal dominant inheritance, with genomic imprinting of the maternal allele for the PGL1 locus [22]. The disease has incomplete penetrance and variable expressivity.

In 2000, linkage analysis and positional cloning allowed Baysal et al. [23] to report the first deleterious mutations in the SDHD gene, corresponding to the PGL1 locus. The use of a candidate gene approach has led to the identification of mutations in SDHC (PGL3)[24] and SDHB (PGL4) [25]. Several mutations in these three genes were subsequently reported in patients with hereditary PGL, and in apparently sporadic cases [26].

Genetics of Hereditary Pheochromocytomas

Prior to 2000, three different familial and syndromic diseases were known to result in adrenomedulla tumors or PHEOs: multiple endocrine neoplasia type II (MEN2; MIM 171400), induced by germline-activating mutations in the RET proto-oncogene [27], von Hippel-Lindau disease (VHL; MIM 193300), due to mutations in the tumor suppressor gene VHL[28], and neurofibromatosis type 1 (MIM 162200), caused by mutations in the NF1 gene [29]. In 2000/2001, the identification of mutations in the SDH (SDHD, SDHB, SDHC) genes in hereditary PGLs (MIM 168000) and in PHEOs led to changes in the genetic counseling and work-up for affected patients [30]. In 2002, Neumann et al. [31] demonstrated the importance of screening for mutations in the genes conferring susceptibility to PHEO in a large, apparently non-syndromic population (271 patients). They reported 24% inherited disease, with 66 patients having a germline mutation in the VHL, RET, SDHD or SDHB gene. Some of these patients had a family history or multifocal disease, identified after genetic testing. In 2003, a retrospective study was performed on 84 patients with apparently sporadic PHEO, from which patients with a family history or syndromic disease were excluded. In this French series, 12% of the patients harbored mutations, mostly in the VHL and SDHB genes [32] (table 2). In this population, followed in a single center for a mean of 9 years, the identification of a mutation in the SDHB gene was associated with a high risk of extra-adrenal location and, particularly, of malignant disease. A preliminary survey of 227 patients with PHEOs from the French cohort showed that one third of these unselected patients had a germline mutation in one of the known susceptibility genes. In two thirds of these cases, the molecular diagnosis was oriented by clinical symptoms or a family history, especially for diseases resulting from inherited mutations in NF1, RET, VHL and SDHD. However, 90% of cases with apparently sporadic presentation are due to mutations in SDHB or VHL[33].

Table 2

Genotyping of pheochromocytoma-susceptibility genes in two different populations

http://www.karger.com/WebMaterial/ShowPic/314431

These recent genetic advances have rapidly led to changes in the management of patients with PHEO. The biological and radiological diagnosis of PHEO in patients of any age should now lead to a search for an inherited disease and the family pedigree should be analyzed. The work-up should comprise (1) a physical examination, including a search for neurofibromas, coffee-colored pigmented spots, and the determination of plasma thyrocalcitonin concentration; (2) a fundoscopic examination looking for retinal hemangioblastomas, and (3) head and neck and abdominal CT or MRI scans to search for cervical PGL, and renal or pancreatic tumors. Targeted genetic testing should be offered to patients with phenotypic features typical of MEN2, VHL disease or hereditary PGL. In patients with a regular, apparently sporadic presentation, the VHL and SDHB genes should be analyzed as a matter of priority.

Genetic Counseling

Genetic testing is indicated for all patients with a PGL and/or a PHEO, whatever the location of the tumor and the age of the subject, but, as discussed above, such testing may also be indicated on the basis of clinical and familial features (fig. 3). Phenotype-genotype correlations are useful for genetic testing, which should initially target the SDHD gene in cases of head and neck PGL, or the SDHB gene in cases of extra-adrenal PGL or PHEO. SDHD gene mutations often result in multiple tumors, primarily in the head and neck. In carriers of SDHB mutations, the resulting tumor is often a functional extra-adrenal PGL or PHEO, which may be malignant [34]. Nonsense and missense mutations, insertions and deletions are frequently encountered in the SDHD and SDHB genes, but only 4 familial cases have so far been linked to the SDHC gene [35]. However,this small number of cases may be accounted for by intragenic deletions of the SDHC gene not detected by direct sequencing [36].

Fig. 3

A family with an SDHD mutation. a Angiography showing bilateral cervical PGL (subject I.1). b The family pedigree, suggesting autosomal dominant transmission with maternal imprinting: subject III.1 had a glomus tumor whereas subject II.1 is asymptomatic. c Analysis of the SDHD gene in the leukocyte DNA of subject I.1 showed a mutation in the SDHD gene affecting its splicing (IVS II–1 G>T).

http://www.karger.com/WebMaterial/ShowPic/314428

The family pedigree may also direct genetic testing. The disease displays autosomal dominant inheritance for the SDHB and SDHC genes, with maternal imprinting for the SDHD gene. Consequently, in families with SDHD mutations, the disease is transmitted exclusively via the father. A heterozygous mother has a 50% risk of transmitting the mutation to her child, but children carrying the maternal mutant allele do not go on to develop the disease. In contrast, the SDHB and SDHC mutations are both maternally and paternally transmitted.

The identification of a causative mutation in an affected patient should lead to presymptomatic familial genetic testing because the early detection of small tumors in individuals at risk can reduce the morbidity of the disease. Presymptomatic genetic testing should be offered to all first-degree relatives if an SDH mutation is detected in the index case. Such testing should make it possible to detect presymptomatic tumors (size <1 cm) in positive carriers, which can be treated surgically with less risk of complication. Several clinical research networks throughout the world focus on hereditary PGL and PHEO. In France, the PGL.NET Network recommends clinical testing including head and neck MRI and metanephrine determination in patients with an SDH mutation. If metanephrine levels are normal, octreotide scintigraphy should be performed to search for non-functional PGLs. If metanephrine levels are high, suggesting a possible functional PGL, 123I-mIBG scintigraphy should be performed to detect the tumor. In Germany and the USA, MRI of the neck, thorax and abdomen-pelvis and/or 18F-DOPA or 18F-dopamine PET are recommended as screening tests [37, 38]. Such tests should be carried out annually for patients with SDHB mutations and every 2 years for patients with SDHD mutations. It is important to note that all these guidelines are empiric and require validation by prospective studies in families with SDH mutations.

SDH Genes and Tumorigenesis

SDH genes (SDHD, SDHC, SDHB) have been shown to be tumor suppressor genes. Consistent with Knudson’s two-hit hypothesis for tumorigenesis involving a tumor suppressor gene, a heterozygous germline mutation in an SDH gene is usually associated with somatic loss of the normal allele (loss of heterozygosity), leading to inactivation of the SDH gene. We have shown that this inactivation results in a total lack of electron transfer from succinate in the tumor [39, 40], for all subunits except SDHA, for which mutations never result in the complete abolition of SDH enzymatic activity (25–50% decrease). The production of fumarate by SDH is immediately followed by the conversion of fumarate into malate by fumarate hydratase (see fig. 1). Mutation of the FH gene, which encodes fumarate hydratase (also known as fumarase), has been found to cause another autosomal disorder characterized by tumors of the skin and uterus and/or renal cancer [3]. These recent discoveries suggest that impairment of the TCA cycle may be involved in cancer [41].

The molecular and cellular mechanisms linking SDH mutations and tumorigenesis remain unknown and experimental models for the study of these disorders have not yet been developed. Several non-mutually exclusive hypotheses have been put forward [2, 42]. They involve a mitochondrial dysfunction leading to resistance to apoptosis, accumulation of oxygen free radicals and oxidative stress, or pseudo-hypoxia acting as a protumoral factor [2]. Hence, in renal cell carcinoma occurring in patients with VHL disease – a known genetic cause of PHEO – it is established that the abnormal stabilization of the hypoxia-inducible factor EPAS1/HIF2α is directly responsible for tumorigenesis [43]. It has therefore been suggested that activation of the hypoxic pathway is also directly involved in the tumorigenic process of SDH-mutated PGLs and PHEOs. Indeed, SDH gene mutations are associated with the induction of hypoxia response genes such as that encoding vascular endothelial growth factor (VEGF), and this induction is thought to be mediated by the abnormal activation of HIF1α and EPAS1/HIF2α (fig. 4). The subsequent stimulation of angiogenesis probably accounts for the high level of vascularization of these tumors [39, 40], but hypoxia-inducible transcription factors (HIFs) may also be responsible for carcinogenesis [for review, see [44]. This hypothesis is supported by the high incidence of head and neck PGLs in populations living at elevated altitude [45]. Several mechanisms accounting for the putative link between SDH mutations and HIF stabilization have been put forward. One is the accumulation of succinate, which would lead to inactivation of the prolyl-4-hydroxylases required for HIF degradation in normoxia [46]; another involves the ROS pathway. The validity of these mechanisms remains to be demonstrated in appropriate experimental models providing an understanding of the molecular and cellular mechanisms involved in the induction of tumorigenesis by SDH mutations.

Fig. 4

Strong expression of genes encoding angiogenic factors in hereditary PGL. (a) EPAS1, (b) VEGF and (c) VEGFR-1 mRNA profiles on in situ hybridization (signal visible as white dots) in a mutated SDHD carotid-body PGL.

http://www.karger.com/WebMaterial/ShowPic/314427

Conclusion

The recent discovery of mutations in the SDHD, SDHC and SDHB genes has shed new light on the primary disorders responsible for PHEOs and PGLs in particular, and more generally, in the elucidation of novel, unexpected oncogenic mechanisms involving mitochondria.


Footnotes

With the support of GIS-Institut des Maladies Rares.


References

  1. Wallace DC: Mitochondrial diseases in man and mouse. Cell 1999;283:1482–1488.
  2. Eng C, Kiuru M, Fernandez MJ, Aaltonen LA: A role for mitochondrial enzymes in inherited neoplasia and beyond. Nat Rev Cancer 2003;3:193–202.
  3. Tomlinson IP, Alam NA, Rowan AJ, Barclay E, Jaeger EE, Kelsell D, Leigh I, Gorman P, Lamlum H, Rahman S, Roylance RR, Olpin S, Bevan S, Barker K, Hearle N, Houlston RS, Kiuru M, Lehtonen R, Karhu A, Vilkki S, Laiho P, Eklund C, Vierimaa O, Aittomaki K, Hietala M, Sistonen P, Paetau A, Salovaara R, Herva R, Launonen V, Aaltonen LA: Multiple Leiomyoma Consortium. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet 2002;30:406–410 [Demonstration of germline heterozygous mutation in the FH mitochondrial gene cause susceptibility to HLRCC].
  4. Rustin P, Munnich A, Rotig A: Succinate dehydrogenase and human diseases: New insights into a well-known enzyme. Eur J Hum Genet 2002;10:289–291.
  5. Ackrell BAC: Cytopathies involving mitochondrial complex II. Mol Aspects Med 2002;23:369–384.
  6. Yankovskaya V, Horsefield R, Tornroth S, Luna-Chavez C, Miyoshi H, Leger C, Byrne B, Cecchini G, Iwata S: Architecture of succinate dehydrogenase and reactive oxygen species generation. Science2003;299:700–704 [Elucidation of the crystal structure of succinate dehydrogenase in E. coli].
  7. Morris AAM, Farnsworth L, Ackrell BAC, Turnbull DM, Birch-Machin MA: The cDNA sequence of the flavoprotein subunit of human heart succinate dehydrogenase. Biochim Biophys Acta1994;1185:125–128.
  8. Kita K, Oya H, Gennis RB, Ackrell BAC, Kasahara M: Human complex II (succinate-ubiquinone oxidoreductase): cDNA cloning of iron sulphur (Ip) subunit of liver mitochondria. Biochem Biophys Res Commun 1990;166:101–108.
  9. Au HC, Ream-Robinson D, Bellew LA, Broomfield PLE, Saghbini M, Scheffler IE: Structural organization of the gene encoding the human iron-sulfur subunit of succinate dehydrogenase. Gene1995;159:249–253.
  10. Hirawake H, Taniwaki M, Tamura A, Kojima S, Kita K: Cytochrome b in human complex II (succinate-ubiquinone oxidoreductase): cDNA cloning of the components in liver mitochondria and chromosome assignment of the genes for the large (SDHC) and small (SDHD) subunits to 1q21 and 11q23. Cytogenet Cell Genet 1997;79:132–138.
  11. Tomitsuka E, Hirawake H, Goto Y, Taniwaki M, Harada S, Kita K: Direct evidence for two distinct forms of the flavoprotein subunit of human mitochondrial complex II (succinate-ubiquinone reductase). J Biochem 2003;134:191–195.
  12. Ishii N, Fujii M, Hartman PS, Tsuda M, Yasuda K, Senoo-Matsuda N, Yanase S, Ayusawa D, Suzuki K: A mutation in succinate dehydrogenase cytochrome b causes oxidative stress and ageing in nematodes. Nature1998;394:694–697.
  13. Bourgeron T, Rustin P, Chretien D, Birch-Machin M, Bourgeois M, Viegas-Pequignot E, Munnich A, Rotig A: Mutation of a nuclear succinate dehydrogenase gene results in mitochondrial respiratory chain deficiency. Nat Genet 1995;11:144–149 [First report of a germline mutation in the SDHA gene causing Leigh syndrome].
  14. Parfait B, Chrétien D, Rötig A, Marsac C, Munnich A, Rustin P: Compound heterozygous mutations in the flavoprotein gene of the respiratory chain complex II in a patient with Leigh syndrome. Hum Genet 2000;106:236–243.
  15. Van Coster R, Seneca S, Smet J, Van Hecke R, Gerlo E, Devreese B, Van Beeumen J, Leroy JG, De Meirleir L, Lissens W: Homozygous Gly555Glu mutation in the nuclear-encoded 70 kDa flavoprotein gene causes instability of the respiratory chain complex II. Am J Med Genet 2003;120A:13–18.
    External Resources
  16. Birch-Machin MA, Taylor RW, Cochran B, Ackrell BA, Turnbull DM: Late-onset optic atrophy, ataxia, and myopathy associated with a mutation of a complex II gene. Ann Neurol 2000;48:330–335.
  17. Rustin P, Rötig A: Inborn errors of complex II – Unusual human mitochondrial diseases. Biochim Biophys Acta 2002;1553:117–122.
  18. Pellitteri PK, Rinaldo A, Myssiorek D, Jackson G, Bradley PJ, Devaney KO, Shaha AR, Netterville JL, Manni JJ, Ferlito A: Paragangliomas of the head and neck. Oral Oncol 2004;40:563–575.
  19. Rao AB, Koeller KK, Adair CF: Paragangliomas of the head and neck: Radiologic-pathologic correlation. Radiographics 1999;19:1605–1632.
  20. Plouin PF, Duclos JM, Soppelsa F, Boublil G, Chatellier G: Factors associated with perioperative morbidity and mortality in patients with pheochromocytoma: Analysis of 165 operations at a single center. J Clin Endocrinol Metab 2001;86:1480–1486.
  21. Van Baars FM, Cremers CWRJ, van den Broek P, Geerts S, Veldman JE: Genetic aspects of non-chromaffin paraganglioma. Hum Genet 1982;60:305–309.
  22. Van der Mey AG, Maaswinkel-Mooy PD, Cornelisse CJ, Schmidt PH, van de Kamp JJ: Genomic imprinting in hereditary glomus tumours: Evidence for new genetic theory. Lancet 1989;2:1291–1294 [Demonstration of the autosomal dominant transmission with maternal genomic imprinting in the head and neck paraganglioma families].
  23. Baysal BE, Ferrell RE, Willett-Brozick JE, Lawrence EC, Myssiorek D, Bosch A, Van der Mey A, Taschner PEM, Rubinstein WS, Myers EN, Richard III CW, Cornelisse CJ, Devilee P, Devlin B: Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science 2000;287:848–851 [Identification of SDHD gene as the causative gene for 11q-linked hereditary paraganglioma families].
  24. Niemann S, Muller U: Mutations in SDHC cause autosomal dominant paraganglioma, type 3. Nat Genet 2000;26:268–270.
  25. Astuti D, Latif F, Dallol A, Dahia PLM, Douglas F, George E, Sköldberg F, Husebye ES, Eng C, Maher ER: Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. Am J Hum Genet 2001;69:49–54 [Demonstration of SDHB gene as a susceptibility gene for familial pheochromocytoma and/or paraganglioma].
  26. Baysal B, Willett-Brozick JE, Lawrence EC, Drovdlic CM, Savul SA, McLeod DR, Yee HA, Brackmann DE, Slattery WH, Myers EN, Ferrell RE, Rubinstein WS: Prevalence of SDHB, SDHC and SDHD germline mutations in clinic patients with head and neck paragangliomas. J Med Genet 2002;39:178–183.
  27. Brandi ML, Gagel RF, Angeli A, Bilezikian JP, Beck-Peccoz P, Bordi C, Conte-Devolx B, Falchetti A, Gheri RG, Libroia A, Lips CJ, Lombardi G, Mannelli M, Pacini F, Ponder BA, Raue F, Skogseid B, Tamburrano G, Thakker RV, Thompson NW, Tomassetti P, Tonelli F, Wells SA Jr, Marx SJ: Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab 2001;86:5658–5671.
  28. Lonser RR, Glenn GM, Walther M, Chew EY, Libutti SK, Linehan WM, Oldfield EH: von Hippel-Lindau disease. Lancet 2003;361:2059–2067.
  29. Reynolds RM, Browning GG, Nawroz I, Campbell IW: Von Recklinghausen’s neurofibromatosis: neurofibromatosis type 1. Lancet 2003;361:1552–1554.
  30. Dluhy RG: Pheochromocytoma – Death of an axiom. N Engl J Med 2002;19:1486–1488.
  31. Neumann HP, Bausch B, McWhinney SR, Bender BU, Gimm O, Franke G, Schipper J, Klisch J, Altehoefer C, Zerres K, Januszewicz A, Eng C, Smith WM, Munk R, Manz T, Glaesker S, Apel TW, Treier M, Reineke M, Walz MK, Hoang-Vu C, Brauckhoff M, Klein-Franke A, Klose P, Schmidt H, Maier-Woelfle M, Peczkowska M, Szmigielski C, Eng C: Freiburg-Warsaw-Columbus Pheochromocytoma Study Group. Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med 2002;346:1459–1466 [Large population study showing that 25% of apparently non-syndromic pheochromocytomas are due to a germline mutation in VHL, RET, SDHB or SDHD genes].
  32. Gimenez-Roqueplo AP, Favier J, Rustin P, Rieubland C, Crespin M, Nau V, Khau Van Kien P, Corvol P, Plouin PF, Jeunemaitre X: COMETE Network. Mutations in the SDHB gene are associated with extra-adrenal and/or malignant phaeochromocytomas. Cancer Res 2003;63:5615–5621 [First demonstration that SDHB mutation is a high risk factor for malignancy and extra-adrenal tumors].
  33. Amar L, Strompf L, Plouin PF, Jeunemaitre X, Gimenez-Roqueplo AP: The SDHB and VHL genes should be systematically tested in patients with nonsyndromic pheochromocytoma. J Hypertens 2004;22(suppl 2):S210.
  34. Neumann HP, Pawlu C, Peczkowska M, Bausch B, McWhinney SR, Muresan M, Buchta M, Franke G, Klisch J, Bley TA, Hoegerle S, Boedeker CC, Opocher G, Schipper J, Januszewicz A, Eng C: European-American Paraganglioma Study Group. Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. JAMA 2004;292:943–951 [Population-based genetic screening for SDHB and SDHD germline mutations from two registries (Germany, Poland)].
  35. Baysal BE: Hereditary paraganglioma targets diverse paraganglia. J Med Genet 2002;39:617–622.
  36. Baysal BE, Willett-Brozick JE, Filho PA, Lawrence EC, Myers EN, Ferrell RE: An Alu-mediated partial SDHC deletion causes familial and sporadic paraganglioma. J Med Genet 2004;41:703–709.
  37. Pacak K, Eisenhofer G, Carrasquillo JA, Chen CC, Li ST, Goldstein DS: 6-[18F] fluorodopamine positron emission tomographic scanning for diagnostic localization of pheochromocytoma. Hypertension 2001;38:6–8.
  38. Hoegerle S, Ghanem N, Altehoefer C, Schipper J, Brink I, Moser E, Neumann HP: 18F-DOPA positron emission tomography for the detection of glomus tumours. 18F-DOPA positron emission tomography for the detection of glomus tumours. Eur J Nucl Med Mol Imaging 2003;30:689–694.
  39. Gimenez-Roqueplo AP, Favier J, Rustin P, Mourad JJ, Plouin PF, Corvol P, Rotig A, Jeunemaitre X: The R22X mutation of the SDHD gene in hereditary paraganglioma abolishes the enzymatic activity of complex II in the mitochondrial respiratory chain and activates the hypoxia pathway. Am J Hum Genet 2001;69:1186–1197 [First demonstration of the loss of SDH enzymatic activity and the stimulation of hypoxia-angiogenic pathway in the SDH-induced tumors].
  40. Gimenez-Roqueplo AP, Favier J, Rustin P, Rieubland C, Kerlan V, Plouin PF, Rotig A, Jeunemaitre X: Functional consequences of a SDHB gene mutation in an apparently sporadic pheochromocytoma. J Clin Endocrinol Metab 2002;87:4771–4774.
  41. Rustin P: Mitochondria, from cell death to proliferation. Nat Genet 2002;30:352–353.
  42. Pollard PJ, Wortham NC, Tomlinson IPM: The TCA cycle and tumorigenesis: The examples of fumarate hydratase and succinate dehydrogenase. Ann Med 2003;35:632–639.
  43. Kondo K, Klco J, Nakamura E, Lechpammer M, Kaelin WG Jr: Inhibition of HIF is necessary for tumor suppression by the von Hippel-Lindau protein. Cancer Cell 2002;1:237–246.
  44. Hopfl G, Ogunshola O, Gassmann M: HIFs and tumors-causes and consequences. Am J Physiol 2004;286:R608–623.
  45. Rodriguez-Cuevas S, Lopez-Garza J, Labastida-Almendaro S: Carotid body tumors in inhabitants of altitudes higher than 2,000 meters above sea level. Head Neck 1998;20:374–378.
  46. Bruick RK: Oxygen sensing in the hypoxic response pathway: Regulation of the hypoxia-inducible transcription factor. Genes Dev 2003;17:2614–2623.

Author Contacts

Dr. Anne-Paule Gimenez-Roqueplo

Département de Génétique, Hôpital Européen Georges Pompidou

20–40, rue Leblanc, FR–75015 Paris (France)

Tel. +33 1 5609 3881, Fax +33 1 5609 3884

E-Mail anne-paule.gimenez@hop.egp.ap-hop-paris.fr


Article / Publication Details

First-Page Preview
Abstract of Mini Review

Received: October 26, 2004
Accepted: February 08, 2005
Published online: June 13, 2005
Issue release date: June 2005

Number of Print Pages: 9
Number of Figures: 4
Number of Tables: 2

ISSN: 1663-2818 (Print)
eISSN: 1663-2826 (Online)

For additional information: http://www.karger.com/HRP


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Wallace DC: Mitochondrial diseases in man and mouse. Cell 1999;283:1482–1488.
  2. Eng C, Kiuru M, Fernandez MJ, Aaltonen LA: A role for mitochondrial enzymes in inherited neoplasia and beyond. Nat Rev Cancer 2003;3:193–202.
  3. Tomlinson IP, Alam NA, Rowan AJ, Barclay E, Jaeger EE, Kelsell D, Leigh I, Gorman P, Lamlum H, Rahman S, Roylance RR, Olpin S, Bevan S, Barker K, Hearle N, Houlston RS, Kiuru M, Lehtonen R, Karhu A, Vilkki S, Laiho P, Eklund C, Vierimaa O, Aittomaki K, Hietala M, Sistonen P, Paetau A, Salovaara R, Herva R, Launonen V, Aaltonen LA: Multiple Leiomyoma Consortium. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet 2002;30:406–410 [Demonstration of germline heterozygous mutation in the FH mitochondrial gene cause susceptibility to HLRCC].
  4. Rustin P, Munnich A, Rotig A: Succinate dehydrogenase and human diseases: New insights into a well-known enzyme. Eur J Hum Genet 2002;10:289–291.
  5. Ackrell BAC: Cytopathies involving mitochondrial complex II. Mol Aspects Med 2002;23:369–384.
  6. Yankovskaya V, Horsefield R, Tornroth S, Luna-Chavez C, Miyoshi H, Leger C, Byrne B, Cecchini G, Iwata S: Architecture of succinate dehydrogenase and reactive oxygen species generation. Science2003;299:700–704 [Elucidation of the crystal structure of succinate dehydrogenase in E. coli].
  7. Morris AAM, Farnsworth L, Ackrell BAC, Turnbull DM, Birch-Machin MA: The cDNA sequence of the flavoprotein subunit of human heart succinate dehydrogenase. Biochim Biophys Acta1994;1185:125–128.
  8. Kita K, Oya H, Gennis RB, Ackrell BAC, Kasahara M: Human complex II (succinate-ubiquinone oxidoreductase): cDNA cloning of iron sulphur (Ip) subunit of liver mitochondria. Biochem Biophys Res Commun 1990;166:101–108.
  9. Au HC, Ream-Robinson D, Bellew LA, Broomfield PLE, Saghbini M, Scheffler IE: Structural organization of the gene encoding the human iron-sulfur subunit of succinate dehydrogenase. Gene1995;159:249–253.
  10. Hirawake H, Taniwaki M, Tamura A, Kojima S, Kita K: Cytochrome b in human complex II (succinate-ubiquinone oxidoreductase): cDNA cloning of the components in liver mitochondria and chromosome assignment of the genes for the large (SDHC) and small (SDHD) subunits to 1q21 and 11q23. Cytogenet Cell Genet 1997;79:132–138.
  11. Tomitsuka E, Hirawake H, Goto Y, Taniwaki M, Harada S, Kita K: Direct evidence for two distinct forms of the flavoprotein subunit of human mitochondrial complex II (succinate-ubiquinone reductase). J Biochem 2003;134:191–195.
  12. Ishii N, Fujii M, Hartman PS, Tsuda M, Yasuda K, Senoo-Matsuda N, Yanase S, Ayusawa D, Suzuki K: A mutation in succinate dehydrogenase cytochrome b causes oxidative stress and ageing in nematodes. Nature1998;394:694–697.
  13. Bourgeron T, Rustin P, Chretien D, Birch-Machin M, Bourgeois M, Viegas-Pequignot E, Munnich A, Rotig A: Mutation of a nuclear succinate dehydrogenase gene results in mitochondrial respiratory chain deficiency. Nat Genet 1995;11:144–149 [First report of a germline mutation in the SDHA gene causing Leigh syndrome].
  14. Parfait B, Chrétien D, Rötig A, Marsac C, Munnich A, Rustin P: Compound heterozygous mutations in the flavoprotein gene of the respiratory chain complex II in a patient with Leigh syndrome. Hum Genet 2000;106:236–243.
  15. Van Coster R, Seneca S, Smet J, Van Hecke R, Gerlo E, Devreese B, Van Beeumen J, Leroy JG, De Meirleir L, Lissens W: Homozygous Gly555Glu mutation in the nuclear-encoded 70 kDa flavoprotein gene causes instability of the respiratory chain complex II. Am J Med Genet 2003;120A:13–18.
    External Resources
  16. Birch-Machin MA, Taylor RW, Cochran B, Ackrell BA, Turnbull DM: Late-onset optic atrophy, ataxia, and myopathy associated with a mutation of a complex II gene. Ann Neurol 2000;48:330–335.
  17. Rustin P, Rötig A: Inborn errors of complex II – Unusual human mitochondrial diseases. Biochim Biophys Acta 2002;1553:117–122.
  18. Pellitteri PK, Rinaldo A, Myssiorek D, Jackson G, Bradley PJ, Devaney KO, Shaha AR, Netterville JL, Manni JJ, Ferlito A: Paragangliomas of the head and neck. Oral Oncol 2004;40:563–575.
  19. Rao AB, Koeller KK, Adair CF: Paragangliomas of the head and neck: Radiologic-pathologic correlation. Radiographics 1999;19:1605–1632.
  20. Plouin PF, Duclos JM, Soppelsa F, Boublil G, Chatellier G: Factors associated with perioperative morbidity and mortality in patients with pheochromocytoma: Analysis of 165 operations at a single center. J Clin Endocrinol Metab 2001;86:1480–1486.
  21. Van Baars FM, Cremers CWRJ, van den Broek P, Geerts S, Veldman JE: Genetic aspects of non-chromaffin paraganglioma. Hum Genet 1982;60:305–309.
  22. Van der Mey AG, Maaswinkel-Mooy PD, Cornelisse CJ, Schmidt PH, van de Kamp JJ: Genomic imprinting in hereditary glomus tumours: Evidence for new genetic theory. Lancet 1989;2:1291–1294 [Demonstration of the autosomal dominant transmission with maternal genomic imprinting in the head and neck paraganglioma families].
  23. Baysal BE, Ferrell RE, Willett-Brozick JE, Lawrence EC, Myssiorek D, Bosch A, Van der Mey A, Taschner PEM, Rubinstein WS, Myers EN, Richard III CW, Cornelisse CJ, Devilee P, Devlin B: Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science 2000;287:848–851 [Identification of SDHD gene as the causative gene for 11q-linked hereditary paraganglioma families].
  24. Niemann S, Muller U: Mutations in SDHC cause autosomal dominant paraganglioma, type 3. Nat Genet 2000;26:268–270.
  25. Astuti D, Latif F, Dallol A, Dahia PLM, Douglas F, George E, Sköldberg F, Husebye ES, Eng C, Maher ER: Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. Am J Hum Genet 2001;69:49–54 [Demonstration of SDHB gene as a susceptibility gene for familial pheochromocytoma and/or paraganglioma].
  26. Baysal B, Willett-Brozick JE, Lawrence EC, Drovdlic CM, Savul SA, McLeod DR, Yee HA, Brackmann DE, Slattery WH, Myers EN, Ferrell RE, Rubinstein WS: Prevalence of SDHB, SDHC and SDHD germline mutations in clinic patients with head and neck paragangliomas. J Med Genet 2002;39:178–183.
  27. Brandi ML, Gagel RF, Angeli A, Bilezikian JP, Beck-Peccoz P, Bordi C, Conte-Devolx B, Falchetti A, Gheri RG, Libroia A, Lips CJ, Lombardi G, Mannelli M, Pacini F, Ponder BA, Raue F, Skogseid B, Tamburrano G, Thakker RV, Thompson NW, Tomassetti P, Tonelli F, Wells SA Jr, Marx SJ: Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab 2001;86:5658–5671.
  28. Lonser RR, Glenn GM, Walther M, Chew EY, Libutti SK, Linehan WM, Oldfield EH: von Hippel-Lindau disease. Lancet 2003;361:2059–2067.
  29. Reynolds RM, Browning GG, Nawroz I, Campbell IW: Von Recklinghausen’s neurofibromatosis: neurofibromatosis type 1. Lancet 2003;361:1552–1554.
  30. Dluhy RG: Pheochromocytoma – Death of an axiom. N Engl J Med 2002;19:1486–1488.
  31. Neumann HP, Bausch B, McWhinney SR, Bender BU, Gimm O, Franke G, Schipper J, Klisch J, Altehoefer C, Zerres K, Januszewicz A, Eng C, Smith WM, Munk R, Manz T, Glaesker S, Apel TW, Treier M, Reineke M, Walz MK, Hoang-Vu C, Brauckhoff M, Klein-Franke A, Klose P, Schmidt H, Maier-Woelfle M, Peczkowska M, Szmigielski C, Eng C: Freiburg-Warsaw-Columbus Pheochromocytoma Study Group. Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med 2002;346:1459–1466 [Large population study showing that 25% of apparently non-syndromic pheochromocytomas are due to a germline mutation in VHL, RET, SDHB or SDHD genes].
  32. Gimenez-Roqueplo AP, Favier J, Rustin P, Rieubland C, Crespin M, Nau V, Khau Van Kien P, Corvol P, Plouin PF, Jeunemaitre X: COMETE Network. Mutations in the SDHB gene are associated with extra-adrenal and/or malignant phaeochromocytomas. Cancer Res 2003;63:5615–5621 [First demonstration that SDHB mutation is a high risk factor for malignancy and extra-adrenal tumors].
  33. Amar L, Strompf L, Plouin PF, Jeunemaitre X, Gimenez-Roqueplo AP: The SDHB and VHL genes should be systematically tested in patients with nonsyndromic pheochromocytoma. J Hypertens 2004;22(suppl 2):S210.
  34. Neumann HP, Pawlu C, Peczkowska M, Bausch B, McWhinney SR, Muresan M, Buchta M, Franke G, Klisch J, Bley TA, Hoegerle S, Boedeker CC, Opocher G, Schipper J, Januszewicz A, Eng C: European-American Paraganglioma Study Group. Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. JAMA 2004;292:943–951 [Population-based genetic screening for SDHB and SDHD germline mutations from two registries (Germany, Poland)].
  35. Baysal BE: Hereditary paraganglioma targets diverse paraganglia. J Med Genet 2002;39:617–622.
  36. Baysal BE, Willett-Brozick JE, Filho PA, Lawrence EC, Myers EN, Ferrell RE: An Alu-mediated partial SDHC deletion causes familial and sporadic paraganglioma. J Med Genet 2004;41:703–709.
  37. Pacak K, Eisenhofer G, Carrasquillo JA, Chen CC, Li ST, Goldstein DS: 6-[18F] fluorodopamine positron emission tomographic scanning for diagnostic localization of pheochromocytoma. Hypertension 2001;38:6–8.
  38. Hoegerle S, Ghanem N, Altehoefer C, Schipper J, Brink I, Moser E, Neumann HP: 18F-DOPA positron emission tomography for the detection of glomus tumours. 18F-DOPA positron emission tomography for the detection of glomus tumours. Eur J Nucl Med Mol Imaging 2003;30:689–694.
  39. Gimenez-Roqueplo AP, Favier J, Rustin P, Mourad JJ, Plouin PF, Corvol P, Rotig A, Jeunemaitre X: The R22X mutation of the SDHD gene in hereditary paraganglioma abolishes the enzymatic activity of complex II in the mitochondrial respiratory chain and activates the hypoxia pathway. Am J Hum Genet 2001;69:1186–1197 [First demonstration of the loss of SDH enzymatic activity and the stimulation of hypoxia-angiogenic pathway in the SDH-induced tumors].
  40. Gimenez-Roqueplo AP, Favier J, Rustin P, Rieubland C, Kerlan V, Plouin PF, Rotig A, Jeunemaitre X: Functional consequences of a SDHB gene mutation in an apparently sporadic pheochromocytoma. J Clin Endocrinol Metab 2002;87:4771–4774.
  41. Rustin P: Mitochondria, from cell death to proliferation. Nat Genet 2002;30:352–353.
  42. Pollard PJ, Wortham NC, Tomlinson IPM: The TCA cycle and tumorigenesis: The examples of fumarate hydratase and succinate dehydrogenase. Ann Med 2003;35:632–639.
  43. Kondo K, Klco J, Nakamura E, Lechpammer M, Kaelin WG Jr: Inhibition of HIF is necessary for tumor suppression by the von Hippel-Lindau protein. Cancer Cell 2002;1:237–246.
  44. Hopfl G, Ogunshola O, Gassmann M: HIFs and tumors-causes and consequences. Am J Physiol 2004;286:R608–623.
  45. Rodriguez-Cuevas S, Lopez-Garza J, Labastida-Almendaro S: Carotid body tumors in inhabitants of altitudes higher than 2,000 meters above sea level. Head Neck 1998;20:374–378.
  46. Bruick RK: Oxygen sensing in the hypoxic response pathway: Regulation of the hypoxia-inducible transcription factor. Genes Dev 2003;17:2614–2623.
ppt logo Download Images (.pptx)


Figures
Thumbnail
Thumbnail
Thumbnail
Thumbnail

Tables
Thumbnail
Thumbnail