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SDHA
succinate dehydrogenase complex flavoprotein subunit A
The SDHA gene provides instructions for making a critical component of the succinate dehydrogenase (SDH) enzyme, vital for cellular energy metabolism and preventing uncontrolled cell growth. The SDHA gene is fundamental for normal cellular function, encoding a subunit of the succinate dehydrogenase enzyme, which plays a dual role in energy conversion pathways within mitochondria.
SDHA is located on the short (p) arm of chromosome 5, at band 5p15.33. Arm ratio per GRCh38 - banding schematic.
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Overview
The SDHA gene, also known as succinate dehydrogenase complex flavoprotein subunit A, is crucial for cellular energy production. It provides the genetic blueprint for one of the four subunits that form the succinate dehydrogenase (SDH) enzyme, a key player in mitochondria. Mitochondria are often called the 'powerhouses' of the cell because they convert energy from food into a usable form.
Beyond its role in energy metabolism, SDHA acts as a tumour suppressor gene. This means it helps to regulate cell growth and division, preventing cells from multiplying uncontrollably. Disruptions in SDHA function can therefore lead to various health conditions, highlighting its importance in maintaining cellular health and preventing disease.
What the gene does
The SDHA gene directs the synthesis of the flavoprotein subunit (Fp) of the succinate dehydrogenase (SDH) enzyme complex. This enzyme is embedded within the inner mitochondrial membrane and connects two essential energy conversion pathways: the citric acid cycle (also known as the Krebs cycle) and oxidative phosphorylation. Within the citric acid cycle, the SDH enzyme facilitates the conversion of succinate into fumarate, a reaction that releases electrons.
The SDHA protein is the catalytically active component responsible for this succinate-to-fumarate conversion and plays a vital role in transferring the released electrons to the oxidative phosphorylation pathway. In oxidative phosphorylation, these electrons contribute to generating an electrical charge, which ultimately drives the production of adenosine triphosphate (ATP), the primary energy currency of the cell.
Additionally, succinate, the compound acted upon by the SDH enzyme, functions as an oxygen sensor within cells. It can activate specific cellular pathways that promote cell growth in low-oxygen environments, a process known as hypoxia. Succinate achieves this by stabilising hypoxia-inducible factor (HIF), a protein that regulates numerous genes involved in cell division and blood vessel formation under hypoxic conditions. As a tumour suppressor, SDHA also contributes to preventing abnormal cell proliferation.
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Chromosome location
The SDHA gene is located on chromosome 5, specifically at position 5p15.33. This precise genomic address indicates its position on the short (p) arm of chromosome 5, within region 15, band 33. The human genome contains over 20,000 genes, and each gene has a specific locus or location on a chromosome. Knowing the chromosomal location helps in understanding its genetic neighbourhood and potential interactions with other genes in that region.
Protein structure
The SDHA protein is composed of 664 amino acids. This protein is a critical component of the succinate dehydrogenase (SDH) complex, which is an enzyme responsible for specific steps in cellular energy production. Domain architecture has not been experimentally characterised in detail for this protein.
Key variants
Variants in the SDHA gene can impact its ability to produce a functional protein, leading to a range of health implications. These genetic changes can alter the structure or function of the succinate dehydrogenase enzyme, affecting cellular energy metabolism and its tumour suppressor capabilities. The clinical consequences of SDHA variants can vary significantly, from benign to pathogenic, depending on the specific alteration and its effect on protein function. Genetic testing for SDHA can identify these variants, providing important information for diagnosis and risk assessment.
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.1012del | p.Ala338fs | Pathogenic | ★★☆☆ | Pheochromocytoma/paraganglioma syndrome 5 |
c.1045_1046del | p.Leu349fs | Pathogenic | ★★☆☆ | Pheochromocytoma/paraganglioma syndrome 5 |
c.1054C>T | p.Arg352Ter | Pathogenic | ★★☆☆ | Mitochondrial complex II deficiency, nuclear type 1 |
c.1054del | p.Arg352fs | Pathogenic/Likely pathogenic | ★★☆☆ | Hereditary cancer-predisposing syndrome |
c.1099C>T | p.Gln367Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Dilated cardiomyopathy 1GG |
c.1123C>T | p.Gln375Ter | Pathogenic | ★★☆☆ | Pheochromocytoma/paraganglioma syndrome 5 |
c.1151C>G | p.Ser384Ter | Pathogenic | ★★☆☆ | Hereditary cancer-predisposing syndrome |
c.1192del | p.Glu398fs | Pathogenic | ★★☆☆ | Mitochondrial complex II deficiency, nuclear type 1 |
c.124_125dup | p.Ala43fs | Pathogenic | ★★☆☆ | Mitochondrial complex II deficiency, nuclear type 1 |
c.1_2del | p.Met1fs | Pathogenic | ★★☆☆ | Pheochromocytoma/paraganglioma syndrome 5 |
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 SDHA gene are associated with several inherited conditions, primarily affecting cellular metabolism and tumour development. These conditions include gastrointestinal stromal tumour (GIST), a type of tumour found in the digestive tract, and nonsyndromic paraganglioma, which are typically non-cancerous tumours associated with the nervous system. SDHA variants are also implicated in hereditary paraganglioma-pheochromocytoma and, in a small number of cases, Leigh syndrome, a severe neurological disorder.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic SDHA variants typically follow autosomal dominant inheritance.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
UK clinical status
The SDHA gene is recognised in the UK National Health Service (NHS) Genomic Medicine Service's PanelApp, indicating its clinical relevance for genetic testing in the UK. It is included in several 'green' gene panels, signifying strong evidence for its association with particular conditions. These panels cover various inherited conditions, including adult solid tumours cancer susceptibility, inherited phaeochromocytoma and paraganglioma, inherited predisposition to GIST, and several mitochondrial disorders.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
While specific lifestyle interventions cannot prevent conditions associated with SDHA variants, general healthy living practices may support overall well-being. A balanced diet, rich in fruits, vegetables, and whole grains, combined with regular physical activity, is generally recommended for maintaining good health. Limiting exposure to environmental toxins and maintaining a healthy weight may also contribute to overall cellular health. these are general population recommendations and not direct treatments or preventions for genetic conditions.
Supplement considerations
There is currently no conclusive evidence that dietary supplements can prevent or treat conditions associated with SDHA gene variants. Some research explores the role of specific nutrients in mitochondrial function, but these findings are not definitively linked to altering the course of genetic conditions caused by SDHA variants. Individuals considering any supplements should consult a healthcare provider to discuss potential benefits and risks, as supplements can interact with medications or have unintended side effects.
Frequently asked questions
What is the primary function of the SDHA gene?
The SDHA gene provides instructions for making a subunit of the succinate dehydrogenase (SDH) enzyme. This enzyme is crucial for two main processes in cellular energy production: the citric acid cycle and oxidative phosphorylation.
What conditions are associated with SDHA gene variants?
Variants in the SDHA gene are linked to conditions such as gastrointestinal stromal tumours (GIST), nonsyndromic paraganglioma, hereditary paraganglioma-pheochromocytoma, and in some cases, Leigh syndrome.
Is SDHA considered a tumour suppressor gene?
Yes, the SDHA gene functions as a tumour suppressor gene. This means it helps prevent cells from growing and dividing in an uncontrolled manner, contributing to the prevention of tumour formation.
Where is the SDHA gene located in the human genome?
The SDHA gene is located on chromosome 5, specifically at the band position 5p15.33.
How does SDHA relate to cellular oxygen sensing?
The succinate compound, acted upon by the SDH enzyme containing the SDHA protein, can act as an oxygen sensor. It helps stabilise hypoxia-inducible factor (HIF), which promotes cell growth and blood vessel formation in low-oxygen conditions.
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
- Korpershoek E, Favier J, Gaal J. SDHA immunohistochemistry detects germline SDHA gene mutations in apparently sporadic paragangliomas and pheochromocytomas. The Journal of clinical endocrinology and metabolism. 2011. PMID: 21752896
- Burnichon N, Brière JJ, Libé R. SDHA is a tumor suppressor gene causing paraganglioma. Human molecular genetics. 2010. PMID: 20484225
- Opocher G, Schiavi F. Genetics of pheochromocytomas and paragangliomas. Best practice & research. Clinical endocrinology & metabolism. 2010. PMID: 21115163
- Qin Y, Buddavarapu K, Dahia PL. Pheochromocytomas: from genetic diversity to new paradigms. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme. 2009. PMID: 19391076
- Horváth R, Abicht A, Holinski-Feder E. Leigh syndrome caused by mutations in the flavoprotein (Fp) subunit of succinate dehydrogenase (SDHA). Journal of neurology, neurosurgery, and psychiatry. 2006. PMID: 16361598
- Parfait B, Chretien D, Rötig A. Compound heterozygous mutations in the flavoprotein gene of the respiratory chain complex II in a patient with Leigh syndrome. Human genetics. 2000. PMID: 10746566