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SDHC
succinate dehydrogenase complex subunit C
The SDHC gene provides instructions for a key component of the succinate dehydrogenase enzyme, which is vital for mitochondrial energy production and acts as a tumour suppressor. The SDHC gene codes for a subunit of the succinate dehydrogenase (SDH) enzyme, which is integral to cellular energy conversion within mitochondria.
SDHC is located on the long (q) arm of chromosome 1, at band 1q23.3. Arm ratio per GRCh38 - banding schematic.
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Overview
The SDHC gene produces one subunit of the four-part succinate dehydrogenase (SDH) enzyme complex [PMID:15580660]. This enzyme is essential for mitochondrial function - the cellular compartments that generate usable energy from nutrients. The protein encoded by SDHC specifically secures the SDH enzyme to the inner membrane of mitochondria, maintaining its proper position for metabolic activity.
In addition to its metabolic duties, the SDHC gene acts as a tumour suppressor, helping to prevent cells from dividing and growing without appropriate regulation [PMID:11157797]. This dual role in energy metabolism and growth control makes SDHC variants clinically significant when they disrupt normal protein function.
What the gene does
The succinate dehydrogenase enzyme containing the SDHC subunit operates at the intersection of two major energy-producing systems: the citric acid cycle and oxidative phosphorylation [PMID:15580660]. During the citric acid cycle, SDH catalyses the transformation of succinate into fumarate, a chemical step that releases electrons - negatively charged particles that carry energy.
These electrons pass through the SDH subunits, travelling from one protein component to another, including through SDHC, before entering the oxidative phosphorylation machinery [PMID:11157797]. This electron movement generates an electrical gradient across the mitochondrial membrane. That gradient drives the synthesis of adenosine triphosphate (ATP), which cells use as their primary fuel source.
Succinate itself serves an additional signalling function beyond its role as an enzyme substrate. Under conditions of low oxygen availability (hypoxia), succinate accumulation prevents the breakdown of hypoxia-inducible factor (HIF), a regulatory protein that ordinarily gets degraded [PMID:15580660]. When HIF remains stable, it activates genes controlling cell proliferation and the development of new blood vessels. The tumour suppressor function of SDHC relates directly to maintaining proper levels of succinate through efficient enzyme activity.
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Chromosome location
The SDHC gene is located on chromosome 1 at position 1q23.3. This particular region on the long arm of chromosome 1 contains the genetic instructions for the SDHC protein.
Protein structure
The SDHC protein is composed of 169 amino acids. Information about its structure can be found in protein databases such as UniProt.
Key variants
Variants within the SDHC gene can alter the protein's structure or function, potentially impacting the efficiency of the succinate dehydrogenase enzyme complex. These genetic changes can range from single nucleotide substitutions to larger deletions or insertions within the gene sequence. Such alterations may lead to reduced enzyme activity, affecting mitochondrial energy production and the gene's tumour suppressor capabilities. The clinical significance of a specific SDHC variant is assessed based on its predicted impact on protein function and its association with inherited conditions.
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.244dupG | - | Pathogenic | ★★☆☆ | Pheochromocytoma/paraganglioma syndrome 3 |
c.118del | p.Arg40fs | Pathogenic | ★★☆☆ | Gastrointestinal stromal tumor |
c.148C>T | p.Arg50Cys | Pathogenic/Likely pathogenic | ★★☆☆ | not specified |
c.17_18dup | p.Arg7Ter | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.177C>A | p.Tyr59Ter | Pathogenic | ★★☆☆ | Gastrointestinal stromal tumor |
c.183G>A | p.Trp61Ter | Pathogenic | ★★☆☆ | Hereditary cancer-predisposing syndrome |
c.1A>C | p.Met1Leu | Pathogenic | ★★☆☆ | Hereditary pheochromocytoma and paraganglioma |
c.1A>G | p.Met1Val | Pathogenic | ★★☆☆ | Pheochromocytoma/paraganglioma syndrome 3 |
c.1A>T | p.Met1Leu | Pathogenic | ★★☆☆ | Pheochromocytoma/paraganglioma syndrome 3 |
c.21-2A>G | - | Pathogenic/Likely pathogenic | ★★☆☆ | Hereditary cancer-predisposing syndrome |
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 the SDHC gene are associated with an increased predisposition to several inherited conditions. These include hereditary paraganglioma-pheochromocytoma type 3, a condition characterised by the development of paragangliomas and pheochromocytomas, which are tumours of the nervous system. Over 30 different genetic changes in the SDHC gene have been identified that raise the risk of developing this condition. Furthermore, alterations in SDHC are implicated in certain gastrointestinal stromal tumours (GISTs), specifically those described as SDH-deficient GISTs, which account for less than 10 percent of GIST cases. SDHC has also been referenced in connection with Cowden syndrome.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic SDHC variants typically follow autosomal dominant inheritance.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
UK clinical status
The SDHC gene is recognised within the UK's genomic healthcare framework. It is currently listed as 'green' on several NHS England National Genomic Test Directory panels. This indicates there is strong evidence for its clinical utility in diagnosing or managing conditions such as adult solid tumours (cancer susceptibility and for rare disease), inherited phaeochromocytoma and paraganglioma (including specific sub-panels like R223 excluding NF1), inherited predisposition to gastrointestinal stromal tumour (R363), multiple endocrine tumours, and neuroendocrine cancer pertinent cancer susceptibility.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
Maintaining a healthy lifestyle is generally recommended for overall well-being, especially for individuals with a genetic predisposition to certain conditions. A balanced diet, regular physical activity, and avoiding smoking can support cellular health. While these general health practices are beneficial, there is no conclusive evidence that specific lifestyle interventions can prevent the development of conditions associated with SDHC gene variants. Regular medical surveillance and adherence to clinical advice are key for managing such predispositions.
Supplement considerations
There is currently no conclusive scientific evidence to suggest that specific dietary supplements can prevent, treat, or mitigate the effects of conditions associated with SDHC gene variants. Individuals considering supplements should consult with a healthcare professional to discuss potential benefits and risks, as some supplements can interact with medications or have adverse effects.
Frequently asked questions
What is the primary function of the SDHC gene?
The SDHC gene provides instructions for a subunit of the succinate dehydrogenase (SDH) enzyme, which is essential for energy production in mitochondria and functions as a tumour suppressor.
What conditions are associated with variations in the SDHC gene?
Variations in the SDHC gene are linked to hereditary paraganglioma-pheochromocytoma, and certain gastrointestinal stromal tumours (GISTs).
How does SDHC act as a tumour suppressor?
The SDHC gene's role in the SDH enzyme helps regulate cellular metabolism and oxygen sensing. When SDHC function is disrupted, succinate can accumulate and stabilise proteins that promote cell division and blood vessel formation, potentially leading to uncontrolled growth.
Is the SDHC gene status relevant for UK clinical care?
Yes, the SDHC gene is included in several NHS England National Genomic Test Directory panels, indicating its importance in the diagnosis and management of conditions like inherited phaeochromocytoma and paraganglioma.
Can lifestyle changes prevent conditions associated with SDHC variants?
While a healthy lifestyle generally supports well-being, there is no definitive evidence that specific lifestyle changes can prevent the development of conditions related to SDHC gene variants. Clinical advice and regular medical surveillance remain crucial.
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
- 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
- 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
- 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
- Niemann S, Müller U. Mutations in SDHC cause autosomal dominant paraganglioma, type 3. Nature genetics. 2000. PMID: 11062460