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SDHAF2
succinate dehydrogenase complex assembly factor 2
The SDHAF2 gene provides instructions for a protein crucial in the assembly of the succinate dehydrogenase (SDH) enzyme complex, which is vital for cellular energy production and tumour suppression. The SDHAF2 gene is responsible for creating a protein that assists in the proper formation and function of the succinate dehydrogenase (SDH) enzyme.
SDHAF2 is located on the long (q) arm of chromosome 11, at band 11q12.2. Arm ratio per GRCh38 - banding schematic.
Explore chromosome 11 in the library →Overview
The SDHAF2 gene, also known as succinate dehydrogenase complex assembly factor 2, is essential for the correct functioning of the succinate dehydrogenase (SDH) enzyme. This enzyme is a critical component of the mitochondrial respiratory chain, which is responsible for cellular energy production.
The SDHAF2 protein facilitates the attachment of a crucial cofactor, FAD, to the SDH enzyme, which is necessary for its enzymatic activity. This process is fundamental for linking the citric acid cycle and oxidative phosphorylation, two vital pathways in cellular metabolism. Beyond energy production, SDHAF2 also acts as a tumour suppressor, helping to prevent uncontrolled cell growth.
What the gene does
The SDHAF2 gene encodes a protein that plays a pivotal role in the assembly and activity of the succinate dehydrogenase (SDH) enzyme complex, also known as complex II. This enzyme is located within the mitochondria, the cell's powerhouses, where it participates in both the citric acid cycle (Krebs cycle) and the electron transport chain.
The primary function of the SDHAF2 protein is to assist in the attachment of flavin adenine dinucleotide (FAD) to the SDH enzyme. FAD acts as a cofactor, meaning it is an essential molecule that helps the enzyme perform its catalytic function. Without proper FAD attachment, the SDH enzyme cannot effectively convert succinate to fumarate within the citric acid cycle.
Furthermore, the SDH enzyme's activity is linked to cellular oxygen sensing. Succinate, the substrate for SDH, can stabilise hypoxia-inducible factor (HIF) in low-oxygen environments. HIF is a protein that regulates genes involved in cell division and new blood vessel formation. By supporting SDH function, SDHAF2 indirectly contributes to the regulation of these pathways, acting as a tumour suppressor by preventing uncontrolled cell proliferation.
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Chromosome location
The SDHAF2 gene is situated on chromosome 11, specifically at position 11q12.2. This location refers to the long (q) arm of chromosome 11, within region 1, band 2, sub-band 2.
Protein structure
Domain architecture has not been experimentally characterised in detail for this protein. The SDHAF2 protein consists of 166 amino acids.
Key variants
Genetic variations within the SDHAF2 gene can impact its ability to produce a functional protein, thereby affecting the proper assembly and activity of the succinate dehydrogenase (SDH) enzyme. These variations may include single nucleotide changes, insertions, or deletions within the gene sequence. Such changes can lead to an altered protein that is less effective or completely non-functional, disrupting cellular energy metabolism and tumour suppression pathways. The clinical implications of specific variants are subject to ongoing research and classification.
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.124del | p.Asp42fs | Pathogenic | ★★☆☆ | Hereditary pheochromocytoma and paraganglioma |
c.130C>T | p.Gln44Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Hereditary cancer-predisposing syndrome |
c.165G>A | p.Trp55Ter | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.166C>T | p.Gln56Ter | Pathogenic | ★★☆☆ | Hereditary cancer-predisposing syndrome |
c.199del | p.Arg67fs | Pathogenic/Likely pathogenic | ★★☆☆ | Hereditary pheochromocytoma and paraganglioma |
c.199dup | p.Arg67fs | Pathogenic | ★★☆☆ | Pheochromocytoma/paraganglioma syndrome 2 |
c.229_230del | p.Arg77fs | Pathogenic/Likely pathogenic | ★★☆☆ | Inherited phaeochromocytoma and paraganglioma excluding NF1 |
c.232G>A | p.Gly78Arg | Pathogenic | ★★☆☆ | Pheochromocytoma/paraganglioma syndrome 2 |
c.267del | p.Phe89fs | Pathogenic/Likely pathogenic | ★★☆☆ | Hereditary pheochromocytoma and paraganglioma |
c.267dup | p.Ala90fs | Pathogenic/Likely pathogenic | ★★☆☆ | Pheochromocytoma/paraganglioma syndrome 2 |
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
Variants in the SDHAF2 gene are associated with hereditary paraganglioma-pheochromocytoma. This condition is characterised by the development of paragangliomas, pheochromocytomas, or both. These are typically non-cancerous tumours that arise from cells of the nervous system.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic SDHAF2 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 SDHAF2 gene is part of several NHS Genomic Medicine Service (GMS) approved panels through PanelApp, indicating its clinical relevance. It is rated 'green' for Adult solid tumours cancer susceptibility, Adult solid tumours for rare disease, Inherited phaeochromocytoma and paraganglioma, Inherited phaeochromocytoma and paraganglioma excluding NF1 (R223), Multiple endocrine tumours, and Neuroendocrine cancer pertinent cancer susceptibility. This signifies that there is sufficient evidence to support its inclusion in these diagnostic panels.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
Maintaining a healthy lifestyle, including a balanced diet and regular physical activity, generally supports overall cellular health and metabolism. While no specific lifestyle interventions have been conclusively shown to prevent conditions associated with SDHAF2 variants, adopting a healthy lifestyle is broadly recommended for its positive impact on well-being. Avoiding factors known to contribute to cancer risk, such as smoking and excessive alcohol consumption, is a general health recommendation.
Supplement considerations
There is currently no conclusive scientific evidence to suggest that specific dietary supplements can prevent, treat, or mitigate conditions associated with SDHAF2 gene variants. Individuals considering any supplements should consult with a healthcare professional to discuss potential benefits, risks, and interactions with other medications or health conditions. Self-medication with supplements is not recommended as a substitute for medical advice or treatment.
Frequently asked questions
What is the primary role of the SDHAF2 gene?
The SDHAF2 gene provides instructions for a protein that helps assemble the succinate dehydrogenase (SDH) enzyme complex. This complex is vital for cellular energy production in the mitochondria and acts as a tumour suppressor.
What condition is associated with variants in the SDHAF2 gene?
Variants in the SDHAF2 gene are primarily associated with hereditary paraganglioma-pheochromocytoma. This condition involves the development of typically non-cancerous tumours in the nervous system.
How does the SDHAF2 protein contribute to energy production?
The SDHAF2 protein assists in attaching the FAD cofactor to the SDH enzyme. This attachment is crucial for the SDH enzyme to function correctly in the citric acid cycle, where it converts succinate to fumarate, a key step in cellular energy metabolism.
Is SDHAF2 considered a tumour suppressor gene?
Yes, the SDHAF2 gene is considered a tumour suppressor. By supporting the proper function of the SDH enzyme, it indirectly helps regulate cellular growth and division, preventing uncontrolled cell proliferation.
Is the SDHAF2 gene included in NHS genetic testing panels?
Yes, the SDHAF2 gene is included in several NHS Genomic Medicine Service (GMS) approved panels, such as those for adult solid tumours cancer susceptibility and inherited phaeochromocytoma and paraganglioma, due to its established clinical relevance.
References
- Müller U. Pathological mechanisms and parent-of-origin effects in hereditary paraganglioma/pheochromocytoma (PGL/PCC). Neurogenetics. 2011. PMID: 21547462
- Bayley JP, Kunst HP, Cascon A. SDHAF2 mutations in familial and sporadic paraganglioma and phaeochromocytoma. The Lancet. Oncology. 2010. PMID: 20071235
- 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
- Hao HX, Khalimonchuk O, Schraders M. SDH5, a gene required for flavination of succinate dehydrogenase, is mutated in paraganglioma. Science (New York, N.Y.). 2009. PMID: 19628817
- 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