Novel germline mutations in the SDHB and SDHD genes in Japanese pheochromocytomas

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

Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma

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.     

Hereditary paraganglioma/pheochromocytoma and inherited succinate dehydrogenase deficiency

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.     

Screening of mutations in genes that predispose to hereditary paragangliomas and pheochromocytomas

Thirty per cent of the paragangliomas and pheochromocytomas reported are hereditary. Mutations in SDHB, SDHC, SDHD, and more recently SDHAF2 and TMEM127 genes have been described in these hereditary tumors. We looked for mutations in these 5 genes in a series of 269 patients with paragangliomas and/or pheochromocytomas. The SDHB, SDHC, and SDHD genes were analyzed in a series of 269 unrelated index patients with paragangliomas and/or pheochromocytomas using dHPLC screening of point mutations followed by direct sequencing and Multiplex PCR Liquid Chromatography to detect large rearrangements confirmed by quantitative PCR. In a second phase, we adapted Multiplex PCR Liquid Chromatography to the SDHAF2 and TMEM127 genes. This method and direct sequencing were applied to 230 patients without the SDHB, C, D mutations. Of the 269 patients, 44 carried a mutation (16.3%). Thirty-seven different mutations were identified: 18 in SDHB (including 2 large deletions), 8 in SDHD, 6 in SDHC, 5 in TMEM127, and no mutations in SDHAF2. Thirteen mutations have not been published so far. An exhaustive study of the different genes is needed to make possible a familial genetic diagnosis in paraganglioma and pheochromocytoma hereditary syndromes. Although mutations in SDHC and TMEM127 are less frequent than mutations in SDHB and SDHD, they also have less evident clinical feature indicators. Analyzing SDHAF2 must be restricted to familial extra-adrenal paragangliomas. Multiplex PCR Liquid Chromatography is a sensitive, fast, and inexpensive method for screening large rearrangements, which are infrequent in these syndromes.     

Early-onset renal cell carcinoma as a novel extraparaganglial component of SDHB-associated heritable paraganglioma

Hereditary paraganglioma syndrome has recently been shown to be caused by germline heterozygous mutations in three (SDHB, SDHC, and SDHD) of the four genes that encode mitochondrial succinate dehydrogenase. Extraparaganglial component neoplasias have never been previously documented. In a population-based registry of symptomatic presentations of phaeochromocytoma/paraganglioma comprising 352 registrants, among whom 16 unrelated registrants were SDHB mutation positive, one family with germline SDHB mutation c.847-50delTCTC had two members with renal cell carcinoma (RCC), of solid histology, at ages 24 and 26 years. Both also had paraganglioma. A registry of early-onset RCCs revealed a family comprising a son with clear-cell RCC and his mother with a cardiac tumor, both with the germline SDHB R27X mutation. The cardiac tumor proved to be a paraganglioma. All RCCs showed loss of the remaining wild-type allele. Our observations suggest that germline SDHB mutations can predispose to early-onset kidney cancers in addition to paragangliomas and carry implications for medical surveillance.     

The mitochondrial SDHD gene is required for early embryogenesis, and its partial deficiency results in persistent carotid body glomus cell activation with full responsiveness to hypoxia

The SDHD gene encodes one of the two membrane-anchoring proteins of the succinate dehydrogenase (complex II) of the mitochondrial electron transport chain. This gene has recently been proposed to be involved in oxygen sensing because mutations that cause loss of its function produce hereditary familiar paraganglioma, a tumor of the carotid body (CB), the main arterial chemoreceptor that senses oxygen levels in the blood. Here, we report the generation of a SDHD knockout mouse, which to our knowledge is the first mammalian model lacking a protein of the electron transport chain. Homozygous SDHD(-/-) animals die at early embryonic stages. Heterozygous SDHD(+/-) mice show a general, noncompensated deficiency of succinate dehydrogenase activity without alterations in body weight or major physiological dysfunction. The responsiveness to hypoxia of CBs from SDHD(+/-) mice remains intact, although the loss of an SDHD allele results in abnormal enhancement of resting CB activity due to a decrease of K(+) conductance and persistent Ca(2+) influx into glomus cells. This CB overactivity is linked to a subtle glomus cell hypertrophy and hyperplasia. These observations indicate that constitutive activation of SDHD(+/-) glomus cells precedes CB tumor transformation. They also suggest that, contrary to previous beliefs, mitochondrial complex II is not directly involved in CB oxygen sensing.     

Loss of SDHB Elevates Catecholamine Synthesis and Secretion Depending on ROS Production and HIF Stabilization

Germline mutations in genes encoding succinate dehydrogenase subunits are associated with the development of familial pheochromocytomas and paragangliomas [hereditary paraganglioma/pheochromocytoma syndrome (HPPS)]. In particular, a mutation in succinate dehydrogenase subunit B (SDHB) is highly associated with abdominal paraganglioma and subsequent distant metastasis (malignant paraganglioma), indicating the importance of SDHB genetic testing. The discovery of HPPS suggests an association among genetic mitochondrial defects, tumor development, and catecholamine oversecretion. To investigate this association, we transfected pheochromocytoma cells (PC12) with SDHB-specific siRNA. SDHB silencing virtually abolished complex II activity, demonstrating the utility of this in vitro model for investigating the pseudo-hypoxic drive hypothesis. Lack of complex II activity resulting from RNA interference of SDHB increased tyrosine hydroxylase (TH; the rate-limiting enzyme in catecholamine biosynthesis) activity and catecholamine secretion. Reduced apoptosis was observed accompanied by Bcl-2 accumulation in PC12 cells, consistent with the phenotypes of paragangliomas with SDHB mutations. In addition, SDHB silencing increased reactive oxygen species (ROS) production and nuclear HIF1α stabilization under normoxic conditions. Furthermore, phenotypes induced by complex II activity knockdown were abolished by pretreatment with N-acetyl cysteine (an ROS scavenger) and by prior HIF1α knockdown, indicating an ROS- and HIF1α-dependent mechanism. Our results indicate that increased ROS may act as signal transduction messengers that induce HIF1α stabilization and may be necessary for the pseudo-hypoxic states observed in our experimental model. To our knowledge, this is the first study demonstrating that pseudo-hypoxic states resulting from SDHB knockdown are associated with increased TH activity and catecholamine oversecretion.     

New insights in the genetics of adrenocortical tumors, pheochromocytomas and paragangliomas.

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.     

Comparison of Pheochromocytomas and Abdominal and Pelvic Paragangliomas with Head and Neck Paragangliomas

ObjectiveTo compare clinical, radiologic, and pathologic characteristics, as well as management and outcomes, in a series of pheochromocytomas, abdominal and pelvic paragangliomas, and pelvic paragangliomas with head and neck paragangliomas.MethodsIn this retrospective study, we reviewed charts of all patients seen at our institution between January 1995 and December 2006. We searched pathology and medical record databases under the terms pheochromocytoma, paraganglioma, head and neck tumors, carotid body tumors, glomus jugulare, and neuroendocrine tumors. We compared clinical, radiologic, and pathologic characteristics, as well as management and outcomes, between patients with pheochromocytoma, abdominal and pelvic paraganglioma, and head and neck paraganglioma.ResultsEighty-six patients were included (46 with head and neck paraganglioma, 23 with pheochromocytoma, and 17 with abdominal or pelvic paraganglioma). Compared with patients with head and neck paraganglioma, patients with pheochromocytoma or abdominal and pelvic paraganglioma were younger (35.7 ± 16 years vs 43 ± 17 years, P = .042) and were more likely to have the classic triad associated with catecholamine hypersecretion of palpitation, excessive sweating, and headache (40% vs 0%, P < .001); hypertension (70% vs 37%, P = .005); and benign tumors (65% vs 43%, P = .03). Patients with head and neck paraganglioma and patients with pheochromocytoma/abdominal and pelvic paraganglioma were not different in female to male ratios (27:19 vs 29:11, respectively, P = .18), tumor size (5.8 ± 2.7 cm vs 5.7 ± 3 cm, respectively; P = .85), or remission rate (43% vs 60%, respectively, P = .13).ConclusionsHead and neck paraganglioma are similar to pheochromocytoma and abdominal and pelvic paraganglioma in size and outcome, but occur at an older age, lack hyperadrenergic manifestations, and are more likely to have local pressure effects and result in persistent disease. (Endocr Pract. 2009;15:194-202)     

A decade (2001-2010) of genetic testing for pheochromocytoma and paraganglioma

The identification of 9 susceptibility genes for paraganglioma/pheochromocytoma between 2001 and 2010 has led to the development of routine genetic tests. To study the evolution in genetic screening for paraganglioma/pheochromocytoma over the past decade, we carried out a retrospective study on the tests performed in our laboratory from January 2001 to December 2010. A genetic test for paraganglioma/pheochromocytoma was assessed for 2 499 subjects, 1 620 index cases, and 879 presymptomatic familial genetic tests. A germline mutation in a PGL/PCC susceptibility gene was identified in 363 index cases (22.4%): 269 in SDHx genes (137 in SDHB, 100 in SDHD, 30 in SDHC, 2 in SDHA), 64 in VHL, 23 in RET, and 7 in TMEM127. A presymptomatic paraganglioma/pheochromocytoma test was positive in 427 subjects. Advances in molecular screening techniques led to an increase in the total number of mutation-carriers diagnosed each year. Overall, during the last decade, our laboratory identified a germline mutation in 44.7% of patients with a suspect hereditary PGL/PCC and in 8% of patients with an apparently sporadic PGL/PCC. During the past decade, the discoveries of new paraganglioma/pheochromocytoma susceptibility genes and the subsequent progress of molecular screening techniques have enabled us to diagnose a hereditary paraganglioma/pheochromocytoma in about 22% of patients tested in routine practice. This genetic testing is of major importance for the follow-up of affected patients and for the genetic counselling of their families.     

Differential impairment of catecholaminergic cell maturation and survival by genetic mitochondrial complex II dysfunction

The SDHD gene (subunit D of succinate dehydrogenase) has been shown to be involved in the generation of paragangliomas and pheochromocytomas. Loss of heterozygosity of the normal allele is necessary for tumor transformation of the affected cells. As complete SdhD deletion is lethal, we have generated mouse models carrying a "floxed" SdhD allele and either an inducible (SDHD-ESR strain) or a catecholaminergic tissue-specific (TH-SDHD strain) CRE recombinase. Ablation of both SdhD alleles in adult SDHD-ESR mice did not result in generation of paragangliomas or pheochromocytomas. In contrast, carotid bodies from these animals showed smaller volume than controls. In accord with these observations, the TH-SDHD mice had decreased cell numbers in the adrenal medulla, carotid body, and superior cervical ganglion. They also manifested inhibited postnatal maturation of mesencephalic dopaminergic neurons and progressive cell loss during the first year of life. These alterations were particularly intense in the substantia nigra, the most affected neuronal population in Parkinson's disease. Unexpectedly, TH(+) neurons in the locus coeruleus and group A13, also lacking the SdhD gene, were unaltered. These data indicate that complete loss of SdhD is not sufficient to induce tumorigenesis in mice. They suggest that substantia nigra neurons are more susceptible to mitochondrial damage than other catecholaminergic cells, particularly during a critical postnatal maturation period.     

A metadata approach for clinical data management in translational genomics studies in breast cancer

Background

Paragangliomas of the head and neck are highly vascular and usually clinically benign tumors arising in the paraganglia of the autonomic nervous system. A significant number of cases (10–50%) are proven to be familial. Multiple genes encoding subunits of the mitochondrial succinate-dehydrogenase (SDH) complex are associated with hereditary paraganglioma: SDHB, SDHC and SDHD. Furthermore, a hereditary paraganglioma family has been identified with linkage to the PGL2 locus on 11q13. No SDH genes are known to be located in the 11q13 region, and the exact gene defect has not yet been identified in this family.

Methods

We have performed a RNA expression microarray study in sporadic, SDHD- and PGL2-linked head and neck paragangliomas in order to identify potential differences in gene expression leading to tumorigenesis in these genetically defined paraganglioma subgroups. We have focused our analysis on pathways and functional gene-groups that are known to be associated with SDH function and paraganglioma tumorigenesis, i.e. metabolism, hypoxia, and angiogenesis related pathways. We also evaluated gene clusters of interest on chromosome 11 (i.e. the PGL2 locus on 11q13 and the imprinted region 11p15).

Results

We found remarkable similarity in overall gene expression profiles of SDHD -linked, PGL2-linked and sporadic paraganglioma. The supervised analysis on pathways implicated in PGL tumor formation also did not reveal significant differences in gene expression between these paraganglioma subgroups. Moreover, we were not able to detect differences in gene-expression of chromosome 11 regions of interest (i.e. 11q23, 11q13, 11p15).

Conclusion

The similarity in gene-expression profiles suggests that PGL2, like SDHD, is involved in the functionality of the SDH complex, and that tumor formation in these subgroups involves the same pathways as in SDH linked paragangliomas. We were not able to clarify the exact identity of PGL2 on 11q13. The lack of differential gene-expression of chromosome 11 genes might indicate that chromosome 11 loss, as demonstrated in SDHD-linked paragangliomas, is an important feature in the formation of paragangliomas regardless of their genetic background.     

Prevalence and spectrum of SDHx mutations in pheochromocytoma and paraganglioma in patients from Belgium: an update

Since the early 2000s, the prevalence and spectrum of mutations in genes encoding subunits of succinate dehydrogenase (SDHx) were reported in large cohorts of patients with pheochromocytoma (PC) and paraganglioma (PGL) from most Western countries. Unfortunately, in Belgium, no equivalent work was performed thus far. Therefore, the aim of the work was to look for mutations in SDHx genes and genotype-phenotype correlations in patients with PC and/or PGL from Belgium. Screening of the coding parts of SDHx genes and deletion search were performed in all patients with PC and/or PGL referred to the -Cliniques Universitaires Saint-Luc from 05/2003 to 05/2011. Genetic screening was performed in 59 unrelated head and neck (hn)PGLs (8 fami-lial) and 53 PCs (7 extra-adrenal; 3 metastatic). In hnPGLs, 10 different SDHD mutations (3 substitutions, 5 deletions, 2 splice site mutations) were detected in 16 patients, including 7 familial cases and 9 apparently sporadic cases. In the same subset, we found 8 different SDHB mutations (5 substitutions, 1 splice site mutation, 1 deletion, 1 duplication) in 10 patients with sporadic hnPGL without evidence of malignancy. No SDHx mutation was detected in patients harboring PCs and no SDHC mutation whatsoever. In conclusion, in our multicentric database of PC-PGLs from Belgium, (i) the prevalence of SDHx mutations was high in hnPGLs (44% in the whole subset, 37% of apparently sporadic cases); (ii) in sporadic cases, the prevalence of SDHB mutations was high (20%), similar to that of SDHD (18%); and (iii) no SDHx mutation was found in a subset of mostly adrenal, benign PCs.     

W43X SDHD mutation in sporadic head and neck paraganglioma

OBJECTIVE: To analyze the presence of SDHD gene mutations in patients with sporadic head and neck paraganglioma. STUDY DESIGN: The presence of somatic and germline SDHD mutations was investigated in 10 patients by polymerase chain reaction and direct sequencing. RESULTS: Two patients displayed mutations: 259C>T (P87S) in 1 case and 129G>A (W43X) in the other. The first was considered a neutral polymorphism. The second was present in the germline of 1 of her sons, who had an apparently unrelated testicular seminoma and loss of heterozygosity (LOH) in the tumor cells. CONCLUSION: This is the first reported case of an SDHD mutation carrier showing LOH in a testicular seminoma.     

Familial Carotid Body Tumors In Patients With Sdhd Mutations: A Case Series

ObjectiveTo describe a family with hereditary paraganglioma due to a disease-causing mutation in the SDHD gene.MethodsWe present the clinical findings, diagnostic test results, treatment, and genetic test results in a family with hereditary paraganglioma.ResultsThree siblings with bilateral carotid body tumors presented at different time points and with varied clinical presentations. While the proband, a 20-year-old man, was not hypertensive and had normal urinary metanephrine and normetanephrine levels, his sister and brother had a more severe clinical picture, with hypertension in both and elevated normetanephrine levels in his brother (his brother had pheochromocytoma and 2 intra-abdominal paragangliomas). Mean age at presentation was 24 years. A 4-base pair frameshift mutation, c.337-340delGACT, was detected in exon 4 of the SDHD gene in all 3 patients.ConclusionThis is the first report of the c.337340delGACT mutation being associated with hereditary paraganglioma; this report emphasizes the need to screen all at-risk first-degree relatives for the disease-causing SDHD mutation once it has been identified in an affected family member. (Endocr Pract. 2012;18:e106-e110)     

Cytologic features of pheochromocytoma and retroperitoneal paraganglioma: a morphologic and immunohistochemical study of 13 cases

OBJECTIVE: To review the cytologic features and potential pitfalls of pheochromocytoma and retroperitoneal paraganglioma and to evaluate complications of the aspiration procedure and the diagnostic utility of immunocytochemistry. STUDY DESIGN: We reviewed 15 cytologic specimens from 12 patients with 13 tumors (1 bilateral case). Ten were adrenal (pheochromocytomas) and 3 extraadrenal paragangliomas. Eleven specimens were from fine needle aspiration (FNA) procedures that were performed in collaboration with radiologists using 23-25-gauge needles. In 3 patients the cytologic material was obtained during intraoperative diagnosis. Immunocytochemistry was performed on alcohol-fixed smears. RESULTS: Two aspirates were hypocellular, while the remainder were cellular. Cells were distributed singly or formed discohesive groups. When present, cytoplasm was abundant and ill defined. Most cells had an eccentric nucleus and plasmacytoid morphology. Nuclear pleomorphism, binucleation and multinucletaion, naked nuclei and intranuclear preudoinclusions were common findings. In 2 cases a lipid background was seen focally. Evident cytoplasmic immunoexpression of synaptophysin or chromogranin was detected in the 10 cases analyzed. One patient developed a hypertensive episode during the FNA procedure. It was controlled medically without complications. CONCLUSION: When adequate cytologic material is present, the recognition of pheochromocytoma and extraadrenal paraganglioma is possible. Together with morphology, immunocytochemical studies allow a specific preoperative diagnosis. Scarce material can be a source of diagnostic errors. FNA of pheochromocytomas is not necessarily contraindicated. When analytic data are not diagnostic, FNA may follow. Aspiration must be performed in an area equipped with the therapeutic tools necessary to control a pheochromocytoma crisis.     

Cytopathies involving mitochondrial complex II

Complex II (succinate-ubiquinone oxidoreductase) is the smallest complex in the respiratory chain and contains four nuclear-encoded subunits SdhA, SdhB, SdhC, and SdhD. It functions both as a respiratory chain component and an essential enzyme of the TCA cycle. Electrons derived from succinate can thus be directly transferred to the ubiquinone pool. Major insights into the workings of complex II have been provided by crystal structures of closely related bacterial enzymes, which have also been genetically manipulated to answer questions of structure-function not approachable using the mammalian system. This information, together with that accrued over the years on bovine complex II and by recent advances in understanding in vivo synthesis of the non-heme iron co-factors of the enzyme, is allowing better recognition of improper functioning of human complex II in diseased states. The discussion in this review is thus limited to cytopathies arising because the enzyme itself is defective or depleted by lack of iron-sulfur clusters. There is a clear dichotomy of effects. Enzyme depletion and mutations in SDHA compromise TCA activity and energy production, whereas mutations in SDHB, SDHC, and SDHD induce paraganglioma. SDHC and SDHD are the first tumor suppressor genes of mitochondrial proteins.     

SDH mutations in cancer

The SDHA, SDHB, SDHC, SDHD genes encode the four subunits of succinate dehydrogenase (SDH; mitochondrial complex II), a mitochondrial enzyme involved in two essential energy-producing metabolic processes of the cell, the Krebs cycle and the electron transport chain. Germline loss-of-function mutations in any of the SDH genes or assembly factor (SDHAF2) cause hereditary paraganglioma/phaeochromocytoma syndrome (HPGL/PCC) through a mechanism which is largely unknown. Owing to the central function of SDH in cellular energy metabolism it is important to understand its role in tumor suppression. Here is reported an overview of genetics, clinical and molecular progress recently performed in understanding the basis of HPGL/PCC tumorigenesis.