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SDHB
succinate dehydrogenase complex iron sulfur subunit B
SDHB encodes an iron-sulphur subunit of succinate dehydrogenase, a mitochondrial enzyme that bridges the citric acid cycle and oxidative phosphorylation while preventing uncontrolled cell growth. The SDHB gene provides instructions for making one of four protein subunits that together form succinate dehydrogenase (SDH), a key enzyme in mitochondrial energy production.
SDHB is located on the short (p) arm of chromosome 1, at band 1p36.13. Arm ratio per GRCh38 - banding schematic.
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Overview
The SDHB gene, located on chromosome 1p36.13, encodes the iron-sulphur subunit B of succinate dehydrogenase, a four-subunit enzyme complex embedded in the inner mitochondrial membrane. Succinate dehydrogenase plays a dual role in cellular metabolism: it participates directly in the citric acid cycle by catalysing the oxidation of succinate to fumarate, and it also functions as Complex II of the electron transport chain, transferring electrons to the oxidative phosphorylation pathway. The SDHB subunit serves as the critical electron acceptor within this enzyme, receiving electrons from the flavoprotein subunit and passing them along to ubiquinone, thereby coupling energy metabolism with ATP synthesis.
Beyond its metabolic function, SDHB operates as a tumour suppressor. When SDH enzyme activity is compromised by pathogenic variants in SDHB, succinate accumulates in the cell, disrupting oxygen-sensing pathways and stabilising hypoxia-inducible factor (HIF) even under normal oxygen conditions. This inappropriate activation of HIF-driven gene programmes promotes blood vessel formation and cell proliferation, creating an environment conducive to tumour development. Consequently, individuals who inherit pathogenic variants in SDHB face substantially elevated risks for paragangliomas and phaeochromocytomas, which are neuroendocrine tumours originating from neural crest-derived tissues.
SDHB is recognised as an actionable secondary finding gene under the American College of Medical Genetics and Genomics (ACMG) guidelines, reflecting the clinical importance of identifying carriers. In the UK, SDHB appears on multiple NHS Genomic Medicine Service gene panels, including those for inherited phaeochromocytoma and paraganglioma, renal cancer susceptibility, and mitochondrial disorders. The gene is inherited in an autosomal dominant pattern, meaning a single pathogenic variant is sufficient to confer increased disease risk, though penetrance is incomplete and tumour development often requires a second somatic event affecting the wild-type allele.
What the gene does
The protein encoded by SDHB consists of 280 amino acids and serves as the iron-sulphur cluster-containing subunit of the succinate dehydrogenase enzyme. This enzyme occupies a unique position in cellular metabolism, functioning both as the sole membrane-bound component of the citric acid cycle and as Complex II of the mitochondrial respiratory chain. Within the citric acid cycle, SDH oxidises succinate to fumarate, releasing electrons in the process. The SDHB subunit captures these electrons through its iron-sulphur clusters and channels them into the electron transport chain, where they ultimately contribute to the proton gradient that drives ATP synthesis.
The iron-sulphur clusters embedded in SDHB are essential for its electron-transfer function. These clusters accept electrons from the flavin adenine dinucleotide (FAD) cofactor bound to the SDHA subunit and relay them sequentially through the protein. The electrons then pass to ubiquinone in the inner mitochondrial membrane, continuing down the respiratory chain. This electron relay is extraordinarily efficient under normal circumstances, but when SDHB function is impaired, the electron flow is disrupted, potentially leading to increased generation of reactive oxygen species and cellular oxidative stress.
SDHB also plays a critical role in cellular oxygen sensing through its influence on succinate homeostasis. Succinate acts as a signalling molecule that modulates the activity of prolyl hydroxylase domain (PHD) enzymes. Under normal oxygen levels, PHD enzymes hydroxylate hypoxia-inducible factor alpha subunits (HIFα), marking them for degradation. When SDH activity is reduced due to SDHB dysfunction, succinate accumulates and competitively inhibits PHD enzymes because succinate and the PHD substrate are structurally similar. This inhibition stabilises HIFα even when oxygen is plentiful, mimicking a hypoxic state. The stabilised HIFα translocates to the nucleus, dimerises with HIFβ, and activates transcription of genes involved in blood vessel formation, glucose metabolism, and cell proliferation - pathways that, when inappropriately activated, can drive tumour formation.
The tumour-suppressor function of SDHB derives from this metabolic-signalling nexus. By maintaining succinate at physiological levels, functional SDHB prevents spurious activation of hypoxia-response pathways. When both copies of SDHB are inactivated in a cell (through germline and somatic events), the resulting pseudohypoxic state promotes a pro-tumourigenic phenotype. Research suggests that this metabolic reprogramming alters the epigenetic landscape of affected cells, as succinate and fumarate can inhibit α-ketoglutarate-dependent dioxygenases, a family of enzymes that includes histone demethylases and DNA demethylases. The resulting epigenetic dysregulation further entrenches the tumourigenic state, illustrating how a defect in a metabolic enzyme can have far-reaching consequences for gene expression and cellular behaviour.
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Chromosome location
SDHB is located on the short arm of chromosome 1 at position 36.13 (1p36.13), a chromosomal region associated with several tumour suppressor genes. The gene spans approximately 35 kilobases of genomic DNA and comprises eight exons that encode the 280-amino-acid iron-sulphur subunit. The 1p36 region is notable for its high gene density and frequent involvement in constitutional deletions associated with developmental disorders, although isolated SDHB variants typically present with tumour predisposition rather than broader syndromic features.
The transcript produced from SDHB undergoes standard post-transcriptional processing, including splicing and polyadenylation, to yield a mature mRNA of roughly 1.2 kilobases. This mRNA is translated in the cytoplasm, and the resulting protein is imported into mitochondria, where it assembles with the other SDH subunits (SDHA, SDHC, and SDHD) at the inner mitochondrial membrane. The assembly process is tightly regulated and requires several assembly factors to ensure proper incorporation of iron-sulphur clusters and correct positioning of the enzyme complex within the membrane.
Protein structure
The SDHB protein is organised into several functionally distinct regions that together enable its role in electron transfer. The 2Fe-2S ferredoxin-type domain, spanning amino acids 40 to 133, coordinates a binuclear iron-sulphur cluster essential for accepting electrons from the SDHA subunit. This domain adopts a characteristic ferredoxin fold, providing a stable scaffold for the metal cluster and ensuring precise positioning relative to the flavin cofactor in SDHA.
Downstream of the 2Fe-2S cluster, the 4Fe-4S ferredoxin-type domain occupies amino acids 176 to 206. This domain harbours a tetranuclear iron-sulphur cluster that serves as an intermediate electron carrier, relaying electrons from the 2Fe-2S cluster towards the ubiquinone-binding site at the SDHB-SDHC interface. The presence of two distinct iron-sulphur clusters within SDHB enables a stepwise, thermodynamically favourable electron-transfer pathway, minimising energy losses and maintaining efficient coupling between the citric acid cycle and the respiratory chain.
Between these two domains lies a region involved in interaction with SDHAF1, an assembly factor required for the proper maturation of the SDH complex. This interaction region, extending from amino acid 146 to 218, overlaps partially with the 4Fe-4S domain and is thought to provide a binding surface for SDHAF1 during the assembly process. SDHAF1 facilitates the insertion of the iron-sulphur clusters into SDHB and may also stabilise the protein during its integration into the SDH complex. Disruption of this interaction region, whether through missense variants or small deletions, can impair SDH assembly and reduce overall enzyme activity, contributing to disease pathogenesis.
The overall architecture of SDHB is highly conserved across species, reflecting the fundamental importance of SDH function in aerobic metabolism. Structural studies have shown that SDHB sits at the interface between the catalytic subunits (SDHA and SDHB) and the membrane-anchoring subunits (SDHC and SDHD), effectively bridging the hydrophilic and hydrophobic compartments of the enzyme complex. This positioning is critical for efficient electron transfer from the site of succinate oxidation to the ubiquinone pool embedded in the lipid bilayer.
Key variants
Pathogenic variants in SDHB are predominantly loss-of-function alterations, including nonsense mutations, frameshift insertions or deletions, splice-site changes, and missense substitutions that disrupt iron-sulphur cluster coordination or protein stability. More than 150 distinct pathogenic variants have been reported in individuals with hereditary paraganglioma-phaeochromocytoma, reflecting considerable allelic heterogeneity. Unlike some tumour suppressor genes where a handful of recurrent mutations account for most cases, pathogenic variants in SDHB are distributed throughout the coding sequence, with no single variant representing a large proportion of cases globally.
Certain populations exhibit founder effects, where a specific SDHB variant is enriched due to shared ancestry. For example, some European populations have recurrent frameshift or nonsense variants that are more commonly observed in regional cohorts. The functional consequences of SDHB variants typically involve reduced or absent SDH enzyme activity, leading to succinate accumulation and downstream metabolic and signalling disruptions. Missense variants affecting the iron-sulphur cluster-binding residues are particularly deleterious, as they abolish electron-transfer capacity even if the protein is otherwise stable and correctly localised.
The incomplete penetrance of SDHB pathogenic variants means that not all carriers will develop tumours, and the age of onset and tumour spectrum can vary even within families carrying the same variant. Environmental factors, genetic modifiers, and stochastic somatic events all contribute to this variability. Tumour formation generally requires both copies of SDHB to be inactivated - one through the inherited pathogenic variant and a second through a later somatic change in the affected tissue. This loss of the remaining functional copy unmasks the cellular defect and triggers tumourigenesis.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.111_112dup | p.Arg38fs | Pathogenic | ★★☆☆ | not provided |
c.118A>G | p.Lys40Glu | Pathogenic/Likely pathogenic | ★★☆☆ | Inherited phaeochromocytoma and paraganglioma excluding NF1 |
c.136C>G | p.Arg46Gly | Pathogenic | ★★☆☆ | Hereditary cancer-predisposing syndrome |
c.136C>T | p.Arg46Ter | Pathogenic | ★★☆☆ | Hereditary cancer-predisposing syndrome |
c.137G>A | p.Arg46Gln | Pathogenic/Likely pathogenic | ★★☆☆ | Hereditary cancer-predisposing syndrome |
c.137G>T | p.Arg46Leu | Pathogenic/Likely pathogenic | ★★☆☆ | Pheochromocytoma |
c.141G>A | p.Trp47Ter | Pathogenic | ★★☆☆ | Pheochromocytoma |
c.143_144dup | p.Pro49fs | Pathogenic | ★★☆☆ | Pheochromocytoma |
c.166_170del | p.Pro56fs | Pathogenic | ★★☆☆ | Hereditary cancer-predisposing syndrome |
c.17_18insACTCTCCTTGAGGCGCCGGTTGC | p.Ala15fs | Pathogenic | ★★☆☆ | Pheochromocytoma |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic variants in SDHB are causally associated with hereditary paraganglioma-phaeochromocytoma (SDHB), an autosomal dominant cancer predisposition syndrome. Individuals with this condition face elevated lifetime risks for paragangliomas, which are neuroendocrine tumours arising from paraganglia (clusters of neural crest-derived cells distributed throughout the body), and phaeochromocytomas, which are paragangliomas specifically located in the adrenal medulla. SDHB-associated tumours can occur in the head and neck region, thorax, abdomen, and pelvis, and they often present at younger ages compared to sporadic cases.
SDHB-related tumours exhibit a higher propensity for malignant behaviour compared to paragangliomas caused by variants in other SDH subunit genes. Metastatic disease occurs in a substantial minority of SDHB carriers who develop paragangliomas, with regional lymph nodes, bones, liver, and lungs being common sites of spread. The aggressive phenotype associated with SDHB underscores the importance of early detection and regular surveillance in known carriers. In addition to paragangliomas and phaeochromocytomas, SDHB pathogenic variants have been identified in a smaller number of individuals with renal cell carcinoma and gastrointestinal stromal tumours (GISTs), particularly in childhood-onset or familial cases. These associations suggest that SDHB-deficient tumourigenesis can manifest in multiple tissue types, though the mechanisms determining tissue specificity remain an area of active investigation.
Inheritance pattern
Conditions caused by pathogenic SDHB variants typically follow autosomal dominant inheritance.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
UK clinical status
Within the NHS Genomic Medicine Service, SDHB is classified with green-level confidence on multiple gene panels, reflecting robust evidence for its clinical validity and utility in the relevant disease contexts. The gene appears on the Inherited phaeochromocytoma and paraganglioma panel and the more restrictive Inherited phaeochromocytoma and paraganglioma excluding NF1 panel (R223), both of which are used to guide diagnostic sequencing and cascade testing in families affected by these neuroendocrine tumours.
SDHB is also included on the Adult solid tumours cancer susceptibility panel and the Adult solid tumours for rare disease panel, acknowledging its role in hereditary cancer syndromes beyond the classic paraganglioma phenotype. The Inherited renal cancer panel and the Renal cancer pertinent cancer susceptibility panel incorporate SDHB due to its association with renal cell carcinoma in a subset of carriers. In recognition of the metabolic dimensions of SDH deficiency, SDHB features on the Mitochondrial disorders panel, the Mitochondrial disorder with complex II deficiency panel (R354), the Likely inborn error of metabolism panel (R98), the Possible mitochondrial disorder - nuclear genes panel (R63), and the Undiagnosed metabolic disorders panel. Additionally, its presence on the Inherited white matter disorders panel and the White matter disorders and cerebral calcification - narrow panel highlights rare presentations involving central nervous system pathology. SDHB is further listed on the Inherited predisposition to GIST panel (R363), the Multiple endocrine tumours panel, and the Neuroendocrine cancer pertinent cancer susceptibility panel, underscoring the breadth of its clinical relevance across oncological and metabolic specialties.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
Individuals who carry a pathogenic SDHB variant are generally advised to adopt lifestyle measures that support overall cardiovascular and metabolic health, though no specific dietary intervention has been conclusively shown to reduce the risk of paraganglioma or phaeochromocytoma development. Eating a varied diet that includes plenty of fruits, vegetables, whole grains, and lean proteins may help support mitochondrial health and cellular resilience against oxidative stress, a feature observed in SDH-deficient cells. Limiting consumption of heavily processed foods and added sugars aligns with broader cancer risk-reduction guidance, although direct evidence connecting these dietary patterns to SDHB-associated tumour outcomes remains limited.
Regular physical activity is associated with improved mitochondrial biogenesis and metabolic health in the general population, and some research suggests that moderate exercise may enhance antioxidant defences. However, physical activity recommendations for SDHB carriers should be individualised, particularly if a phaeochromocytoma is present or suspected, as these tumours can cause episodic catecholamine release leading to hypertensive crises during exertion. Carriers who have not yet developed tumours may benefit from routine exercise within the bounds of their overall health status, but any new exercise regimen should be discussed with a healthcare provider familiar with the individual's clinical history.
Alcohol consumption and smoking are established risk factors for various cancers, and while specific data linking these exposures to SDHB-associated tumourigenesis are limited, it is prudent for carriers to minimise or avoid tobacco use and consume alcohol in moderation, if at all. Some observational studies indicate that smoking may exacerbate oxidative stress and interfere with cellular oxygen sensing, pathways that are already perturbed in SDH-deficient contexts. Stress management and adequate sleep are also important components of a health-promoting lifestyle, as chronic stress and sleep deprivation can adversely affect metabolic regulation and immune surveillance. Carriers should engage in open dialogue with their clinical team to tailor lifestyle recommendations to their individual risk profile and surveillance schedule.
Supplement considerations
There is currently no conclusive evidence that any dietary supplement can prevent the development of paragangliomas or phaeochromocytomas in individuals with pathogenic SDHB variants. Antioxidant supplements, such as vitamins C and E, coenzyme Q10, and alpha-lipoic acid, are sometimes discussed in the context of mitochondrial support, given that SDH deficiency can increase reactive oxygen species production. However, clinical trials have not demonstrated that antioxidant supplementation reduces tumour risk in SDHB carriers, and some studies in other contexts have raised concerns about high-dose antioxidants potentially interfering with cancer therapies or even promoting tumour growth under certain conditions.
Coenzyme Q10 is occasionally considered because of its role in the electron transport chain, but there is no robust evidence that exogenous CoQ10 supplementation compensates for impaired SDH activity or alters clinical outcomes in SDHB-related disease. Similarly, while some mitochondrial disorder patients benefit from cofactor supplementation (such as riboflavin for specific flavoprotein deficiencies), SDHB deficiency generally does not respond to such interventions, as the primary defect lies in the structural integrity and assembly of the SDH complex rather than cofactor availability.
Before starting any supplement regimen, individuals with pathogenic SDHB variants should consult a healthcare provider with expertise in inherited cancer syndromes or metabolic disorders. Dietary supplements may interact with medications, affect biochemical test results, and in some instances could be contraindicated in the presence of particular tumours or during active treatment. The decision to use any supplement should be informed by the individual's clinical status and surveillance findings, ensuring that supplementation is safe and appropriately monitored.
Frequently asked questions
What does the SDHB gene do?
SDHB encodes an iron-sulphur subunit of succinate dehydrogenase, an enzyme that links the citric acid cycle to the electron transport chain in mitochondria. It also functions as a tumour suppressor by regulating cellular oxygen-sensing pathways.
How are SDHB variants inherited?
Pathogenic SDHB variants are inherited in an autosomal dominant pattern, meaning a single altered copy can confer increased cancer risk. Not all carriers develop tumours, as penetrance is incomplete and additional somatic events are typically required for tumour formation.
What types of tumours are associated with SDHB?
SDHB pathogenic variants are most commonly associated with paragangliomas and phaeochromocytomas, neuroendocrine tumours that can occur in various body sites. Carriers also have elevated risks for renal cell carcinoma and, less commonly, gastrointestinal stromal tumours.
Why are SDHB-related tumours more aggressive?
Tumours arising in SDHB carriers exhibit a higher rate of malignant behaviour and metastasis compared to paragangliomas caused by variants in other SDH genes. The reasons for this increased aggressiveness are not fully understood but may relate to the degree of metabolic disruption and pseudohypoxic signalling.
Should SDHB carriers undergo regular screening?
Clinical guidelines generally recommend regular biochemical testing and imaging surveillance for SDHB carriers to enable early detection of tumours. The specific screening protocol should be determined by a specialist familiar with hereditary paraganglioma-phaeochromocytoma syndromes.
Can lifestyle changes reduce tumour risk in SDHB carriers?
While a healthy lifestyle supporting cardiovascular and metabolic health is advisable, there is no proven intervention that eliminates tumour risk in SDHB carriers. Regular surveillance and clinical management remain the cornerstones of care.
References
- Gill AJ. Succinate dehydrogenase (SDH)-deficient neoplasia. Histopathology. 2018. PMID: 29239034
- Belinsky MG, Rink L, von Mehren M. Succinate dehydrogenase deficiency in pediatric and adult gastrointestinal stromal tumors. Frontiers in oncology. 2013. PMID: 23730622
- Ni Y, He X, Chen J. Germline SDHx variants modify breast and thyroid cancer risks in Cowden and Cowden-like syndrome via FAD/NAD-dependant destabilization of p53. Human molecular genetics. 2012. PMID: 21979946
- Janeway KA, Kim SY, Lodish M. Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations. Proceedings of the National Academy of Sciences of the United States of America. 2011. PMID: 21173220
- Gill AJ, Pachter NS, Clarkson A. Renal tumors and hereditary pheochromocytoma-paraganglioma syndrome type 4. The New England journal of medicine. 2011. PMID: 21366490
- Müller U. Pathological mechanisms and parent-of-origin effects in hereditary paraganglioma/pheochromocytoma (PGL/PCC). Neurogenetics. 2011. PMID: 21547462
- Burnichon N, Rohmer V, Amar L. The succinate dehydrogenase genetic testing in a large prospective series of patients with paragangliomas. The Journal of clinical endocrinology and metabolism. 2009. PMID: 19454582
- Pasini B, Stratakis CA. SDH mutations in tumorigenesis and inherited endocrine tumours: lesson from the phaeochromocytoma-paraganglioma syndromes. Journal of internal medicine. 2009. PMID: 19522823
- Stratakis CA, Carney JA. The triad of paragangliomas, gastric stromal tumours and pulmonary chondromas (Carney triad), and the dyad of paragangliomas and gastric stromal sarcomas (Carney-Stratakis syndrome): molecular genetics and clinical implications. Journal of internal medicine. 2009. PMID: 19522824
- Pasini B, McWhinney SR, Bei T. Clinical and molecular genetics of patients with the Carney-Stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDHC, and SDHD. European journal of human genetics : EJHG. 2008. PMID: 17667967
- Ni Y, Zbuk KM, Sadler T. Germline mutations and variants in the succinate dehydrogenase genes in Cowden and Cowden-like syndromes. American journal of human genetics. 2008. PMID: 18678321
- Ricketts C, Woodward ER, Killick P. Germline SDHB mutations and familial renal cell carcinoma. Journal of the National Cancer Institute. 2008. PMID: 18728283
- Selak MA, Armour SM, MacKenzie ED. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer cell. 2005. PMID: 15652751
- Pollard PJ, Brière JJ, Alam NA. Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations. Human molecular genetics. 2005. PMID: 15987702
- Vanharanta S, Buchta M, McWhinney SR. Early-onset renal cell carcinoma as a novel extraparaganglial component of SDHB-associated heritable paraganglioma. American journal of human genetics. 2004. PMID: 14685938
- Neumann HP, Bausch B, McWhinney SR. Germ-line mutations in nonsyndromic pheochromocytoma. The New England journal of medicine. 2002. PMID: 12000816
- Astuti D, Latif F, Dallol A. Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. American journal of human genetics. 2001. PMID: 11404820