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SDHD
succinate dehydrogenase complex subunit D
The SDHD gene provides instructions for a key component of the succinate dehydrogenase enzyme complex, essential for cellular energy conversion within mitochondria. The SDHD gene encodes a subunit of the succinate dehydrogenase (SDH) enzyme, which is vital for both the citric acid cycle and oxidative phosphorylation in cellular respiration.
SDHD is located on the long (q) arm of chromosome 11, at band 11q23.1. Arm ratio per GRCh38 - banding schematic.
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Overview
The SDHD gene, or succinate dehydrogenase complex subunit D, is fundamental to cellular metabolism and energy production. It provides the genetic blueprint for one of four subunits that make up the succinate dehydrogenase (SDH) enzyme complex, located within the mitochondria of cells.
This enzyme complex plays a dual role, participating in two critical metabolic pathways: the citric acid cycle (also known as the Krebs cycle) and the electron transport chain (oxidative phosphorylation). Beyond its role in energy, SDHD also functions as a tumour suppressor gene, helping to prevent uncontrolled cell growth and division. Variants in SDHD can therefore disrupt these vital cellular processes, contributing to the development of certain inherited conditions.
What the gene does
The SDHD gene is responsible for producing the D subunit of the succinate dehydrogenase (SDH) enzyme complex, an integral component of mitochondrial function. Mitochondria are often referred to as the 'powerhouses' of the cell, where food energy is converted into a usable form for cellular activities.
The SDH enzyme complex acts as a crucial link between two major energy-generating pathways: the citric acid cycle and oxidative phosphorylation. Within the citric acid cycle, the SDH enzyme facilitates the conversion of succinate into fumarate. This reaction releases electrons, which are then transferred through the various SDH subunits, including the protein produced by the SDHD gene, to the oxidative phosphorylation pathway.
In oxidative phosphorylation, the flow of these electrons generates an electrochemical gradient, which is then harnessed to produce adenosine triphosphate (ATP), the cell's primary energy currency. The SDHD protein specifically helps to anchor the entire SDH enzyme complex within the inner mitochondrial membrane, ensuring its proper positioning and function in this electron transfer process.
Furthermore, the substrate succinate, upon which the SDH enzyme acts, is recognised as an oxygen sensor within the cell. Elevated levels of succinate, which can occur if the SDH enzyme is not functioning correctly, can stabilise a protein called hypoxia-inducible factor (HIF). HIF plays a critical role in activating genes involved in cell division and new blood vessel formation, particularly in environments with low oxygen. By preventing the normal breakdown of HIF, an impaired SDH complex can inadvertently promote cell growth, highlighting SDHD's additional role as a tumour suppressor gene, meaning it helps to prevent uncontrolled cell proliferation.
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Chromosome location
The SDHD gene is located on chromosome 11 at position 11q23.1. This specifies its precise address on the long arm ('q') of chromosome 11, within region 23 and sub-band 1. The gene encodes a protein composed of 159 amino acids.
Protein structure
Domain architecture has not been experimentally characterised in detail for this protein.
Key variants
Variants in the SDHD gene can alter the normal function of the succinate dehydrogenase enzyme complex. These genetic changes can range from single nucleotide substitutions to larger deletions or duplications. Pathogenic variants typically lead to a reduction in the enzyme's activity or its stability, impairing cellular energy production and potentially disrupting oxygen sensing mechanisms within the cell. Given SDHD's role as a tumour suppressor, such variants can increase an individual's predisposition to developing specific tumour types.
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.106C>T | p.Gln36Ter | Pathogenic | ★★☆☆ | Pheochromocytoma/paraganglioma syndrome 1 |
c.112C>T | p.Arg38Ter | Pathogenic | ★★☆☆ | Pheochromocytoma/paraganglioma syndrome 1 |
c.113_116dup | p.Ile40fs | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.129G>A | p.Trp43Ter | Pathogenic | ★★☆☆ | Pheochromocytoma/paraganglioma syndrome 1 |
c.13_14del | p.Trp5fs | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.135_160del | p.Val46fs | Pathogenic | ★★☆☆ | Hereditary cancer-predisposing syndrome |
c.139C>T | p.Gln47Ter | Pathogenic | ★★☆☆ | not provided |
c.144_145dup | p.Ile49fs | Pathogenic | ★★☆☆ | Cowden syndrome 3 |
c.147dup | p.His50fs | Pathogenic/Likely pathogenic | ★★☆☆ | Hereditary cancer-predisposing syndrome |
c.14G>A | p.Trp5Ter | 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 the SDHD gene are primarily associated with hereditary paraganglioma, an inherited condition characterised by the development of neuroendocrine tumours. These tumours can occur in various locations, particularly in the head and neck. Additionally, SDHD variants are linked to a rare form of gastrointestinal stromal tumour (GIST), known as SDH-deficient GIST, which typically affects the stomach and often presents in younger individuals. Some cases of nonsyndromic paraganglioma, where there is no family history of such tumours, have also been attributed to SDHD variants.
Inheritance pattern
Conditions caused by pathogenic SDHD variants typically follow autosomal dominant inheritance.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
UK clinical status
In the UK, the SDHD gene is recognised as clinically actionable by NHS England's National Genomic Test Directory. It is included on several gene panels related to inherited cancer susceptibilities and metabolic disorders. Specifically, SDHD is assessed on panels for adult solid tumours cancer susceptibility, inherited phaeochromocytoma and paraganglioma (including a specific panel excluding NF1), inherited predisposition to GIST, and various mitochondrial disorder panels. This widespread inclusion underscores the gene's importance in diagnosing and managing these conditions within the NHS.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
Maintaining a healthy lifestyle may support overall well-being for individuals with a genetic predisposition due to SDHD variants, though no specific lifestyle interventions are known to prevent paragangliomas or GISTs directly. Research suggests that a balanced diet rich in fruits, vegetables, and whole grains, along with regular physical activity, can contribute to general health and may help manage co-morbidities. Limiting exposure to environmental toxins and avoiding smoking are also generally recommended for their broad health benefits. Individuals with SDHD variants should consult their healthcare provider for personalised advice, particularly regarding tumour surveillance and management strategies, as these are critical for early detection and intervention.
Supplement considerations
There is currently no conclusive scientific evidence to suggest that specific dietary supplements can prevent the development or progression of conditions associated with SDHD gene variants, such as paragangliomas or gastrointestinal stromal tumours. While some supplements are marketed for general cellular health or antioxidant properties, their direct impact on SDHD-related conditions has not been established through rigorous clinical trials. Individuals considering any supplements should discuss this with their healthcare provider to ensure safety and avoid potential interactions with ongoing medical management. This is especially important given the complex metabolic and tumour-suppressing roles of the SDHD gene.
Frequently asked questions
What is the primary function of the SDHD gene?
The SDHD gene provides instructions for a subunit of the succinate dehydrogenase (SDH) enzyme, which is crucial for cellular energy production within mitochondria, connecting the citric acid cycle and oxidative phosphorylation.
What conditions are associated with variants in the SDHD gene?
Variants in the SDHD gene are primarily associated with hereditary paraganglioma, a type of neuroendocrine tumour, and a rare form of gastrointestinal stromal tumour (GIST) known as SDH-deficient GIST.
How is SDHD inherited?
SDHD-related conditions are typically inherited in an autosomal dominant pattern. This means that inheriting just one copy of a pathogenic variant in the SDHD gene is sufficient to increase an individual's risk of developing the associated conditions.
Is the SDHD gene considered a tumour suppressor?
Yes, the SDHD gene functions as a tumour suppressor. It plays a role in preventing uncontrolled cell growth and division, and when its function is impaired by pathogenic variants, it can contribute to tumour development.
What are paragangliomas?
Paragangliomas are generally non-cancerous tumours that originate from specific nerve cells and are typically associated with the nervous system. They can occur in various parts of the body, particularly in the head, neck, and abdomen.
Is SDHD included in NHS genetic testing?
Yes, the SDHD gene is included on several NHS England National Genomic Test Directory panels, particularly for inherited cancer susceptibilities such as phaeochromocytoma and paraganglioma, and specific types of gastrointestinal stromal tumours.
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
- Müller U. Pathological mechanisms and parent-of-origin effects in hereditary paraganglioma/pheochromocytoma (PGL/PCC). Neurogenetics. 2011. PMID: 21547462
- Ayala-Ramirez M, Callender GG, Kupferman ME. Paraganglioma syndrome type 1 in a patient with Carney-Stratakis syndrome. Nature reviews. Endocrinology. 2010. PMID: 20098451
- 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
- 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
- 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
- Douwes Dekker PB, Hogendoorn PC, Kuipers-Dijkshoorn N. SDHD mutations in head and neck paragangliomas result in destabilization of complex II in the mitochondrial respiratory chain with loss of enzymatic activity and abnormal mitochondrial morphology. The Journal of pathology. 2003. PMID: 14595761
- Neumann HP, Bausch B, McWhinney SR. Germ-line mutations in nonsyndromic pheochromocytoma. The New England journal of medicine. 2002. PMID: 12000816
- Gimenez-Roqueplo AP, Favier J, Rustin P. 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. American journal of human genetics. 2001. PMID: 11605159
- Gimm O, Armanios M, Dziema H. Somatic and occult germ-line mutations in SDHD, a mitochondrial complex II gene, in nonfamilial pheochromocytoma. Cancer research. 2000. PMID: 11156372