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FH
fumarate hydratase
The FH gene provides instructions for producing the fumarate hydratase enzyme, which is vital for cellular energy metabolism and plays a role in various inherited conditions, including certain cancer predisposition syndromes. The FH gene is responsible for encoding fumarate hydratase, an enzyme integral to the citric acid cycle, a fundamental process for generating cellular energy.
FH is located on the long (q) arm of chromosome 1, at band 1q43. Arm ratio per GRCh38 - banding schematic.
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Overview
The FH gene, also known as fumarate hydratase, provides the genetic blueprint for an enzyme called fumarase. This enzyme is a critical component of the citric acid cycle (also known as the Krebs cycle), a series of biochemical reactions that enable cells to use oxygen and produce energy. Specifically, fumarase facilitates the conversion of fumarate into malate, two key molecules within this metabolic pathway.
Dysfunction of the FH gene can lead to a build-up of fumarate within cells, which may have detrimental effects. Inherited alterations in the FH gene are associated with several conditions, including the severe metabolic disorder fumarase deficiency, and an increased susceptibility to certain cancers, notably Hereditary Leiomyomatosis and Renal Cell Carcinoma (HLRCC).
What the gene does
The primary function of the FH gene is to direct the synthesis of the fumarase enzyme, which is indispensable for cellular energy production. Fumarase participates in the citric acid cycle, an essential metabolic pathway occurring within the mitochondria of cells. During this cycle, fumarase catalyses the reversible hydration of fumarate to malate.
This specific enzymatic step is crucial for maintaining the flow of metabolites through the citric acid cycle, which ultimately leads to the generation of adenosine triphosphate (ATP), the main energy currency of the cell. Disruptions to this enzymatic activity, often due to pathogenic variants in the FH gene, can impair energy metabolism and lead to an accumulation of fumarate. Elevated fumarate levels are thought to contribute to cellular stress and may drive the development of associated conditions by altering specific cellular signalling pathways.
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Chromosome location
The FH gene is situated on the long arm of chromosome 1, at position 1q43. This specific genomic location indicates its address within the human genome. The gene spans a particular region of DNA that contains the instructions for making the fumarase enzyme.
Protein structure
The fumarate hydratase protein consists of 510 amino acids. Domain architecture has not been experimentally characterised in detail for this protein.
Key variants
Variants within the FH gene can range from benign changes with no clinical effect to pathogenic alterations that disrupt the normal function of the fumarase enzyme. These variations typically involve single nucleotide changes that can alter the amino acid sequence of the protein, or larger deletions or insertions within the gene. Over 90 distinct FH gene variants have been identified that are associated with inherited conditions. The clinical significance of a specific FH gene variant is determined through careful evaluation, often involving genetic testing and clinical 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.1392delG | - | Pathogenic | ★★☆☆ | not provided |
c.556_557delAG | - | Pathogenic | ★★☆☆ | Hereditary cancer-predisposing syndrome |
c.1000dup | p.Ser334fs | Pathogenic | ★★☆☆ | Hereditary cancer-predisposing syndrome |
c.1020T>A | p.Asn340Lys | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.1021G>A | p.Asp341Asn | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.1023T>G | p.Asp341Glu | Pathogenic | ★★☆☆ | Hereditary cancer-predisposing syndrome |
c.1027C>T | p.Arg343Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Hereditary leiomyomatosis and renal cell cancer |
c.1037G>A | p.Gly346Asp | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.1041del | p.Gly348fs | Pathogenic | ★★☆☆ | Hereditary leiomyomatosis and renal cell cancer |
c.1052C>A | p.Ser351Ter | Pathogenic | ★★☆☆ | not provided |
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 FH gene are primarily associated with two distinct inherited conditions. One is fumarase deficiency, a severe metabolic disorder that predominantly affects the brain and is often fatal in infancy. The other major condition is Hereditary Leiomyomatosis and Renal Cell Carcinoma (HLRCC), an autosomal dominant syndrome characterised by a predisposition to benign smooth muscle tumours (leiomyomas) in the skin and uterus, and an increased risk of developing aggressive kidney cancer.
Inheritance pattern
Conditions caused by pathogenic FH variants typically follow autosomal dominant inheritance.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
UK clinical status
The FH gene is included in several expert-curated panels within the NHS Genomic Medicine Service's PanelApp. This inclusion highlights its significance in clinical genomics for patients in the UK. The gene is part of panels related to Adult solid tumours cancer susceptibility, Fumarate hydratase-related tumour syndromes (R365), Inherited renal cancer (R224), and Intellectual disability, among others, reflecting its broad clinical relevance.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
Research suggests that maintaining a generally healthy lifestyle, including a balanced diet and regular physical activity, supports overall cellular health. While specific lifestyle interventions cannot prevent the onset of conditions associated with FH gene variants, these general recommendations may contribute to well-being. For individuals with an FH gene variant, discussions about lifestyle should always occur within the context of their specific medical management plan, guided by healthcare professionals.
Supplement considerations
Currently, there is no conclusive scientific evidence to suggest that specific dietary supplements can prevent or treat conditions associated with FH gene variants. Individuals considering any supplements should consult with a healthcare provider to discuss potential benefits, risks, and interactions, especially given the complex metabolic roles of the fumarase enzyme.
Frequently asked questions
What is the main role of the FH gene?
The FH gene provides instructions for making the fumarase enzyme, which is essential for the citric acid cycle. This cycle is a fundamental process that allows cells to generate energy by converting fumarate to malate.
What conditions are associated with FH gene variants?
Variants in the FH gene are primarily associated with two conditions: fumarase deficiency, a severe metabolic disorder, and Hereditary Leiomyomatosis and Renal Cell Carcinoma (HLRCC), which increases the risk of benign tumours and kidney cancer.
How is the FH gene involved in cancer?
Pathogenic variants in the FH gene are linked to Hereditary Leiomyomatosis and Renal Cell Carcinoma (HLRCC), a syndrome that increases an individual's susceptibility to developing kidney cancer and benign smooth muscle tumours.
Is the FH gene included in UK genetic testing panels?
Yes, the FH gene is listed in several panels on the NHS Genomic Medicine Service's PanelApp, indicating its relevance for genetic testing in the UK for conditions like cancer susceptibility and metabolic disorders.
Can lifestyle changes prevent FH-related conditions?
While a generally healthy lifestyle supports overall well-being, there is no evidence that specific lifestyle changes can prevent the onset of conditions caused by FH gene variants. Any health decisions should be made in consultation with a healthcare professional.
References
- Picaud S, Kavanagh KL, Yue WW. Structural basis of fumarate hydratase deficiency. Journal of inherited metabolic disease. 2011. PMID: 21445611
- Ottolenghi C, Hubert L, Allanore Y. Clinical and biochemical heterogeneity associated with fumarase deficiency. Human mutation. 2011. PMID: 21560188
- Lorenzato A, Olivero M, Perro M. A cancer-predisposing "hot spot" mutation of the fumarase gene creates a dominant negative protein. International journal of cancer. 2008. PMID: 17960613
- Raimundo N, Ahtinen J, Fumić K. Differential metabolic consequences of fumarate hydratase and respiratory chain defects. Biochimica et biophysica acta. 2008. PMID: 18313410
- Bayley JP, Launonen V, Tomlinson IP. The FH mutation database: an online database of fumarate hydratase mutations involved in the MCUL (HLRCC) tumor syndrome and congenital fumarase deficiency. BMC medical genetics. 2008. PMID: 18366737
- Sudarshan S, Linehan WM, Neckers L. HIF and fumarate hydratase in renal cancer. British journal of cancer. 2007. PMID: 17211469
- Sudarshan S, Pinto PA, Neckers L. Mechanisms of disease: hereditary leiomyomatosis and renal cell cancer--a distinct form of hereditary kidney cancer. Nature clinical practice. Urology. 2007. PMID: 17287871
- Ratcliffe PJ. Fumarate hydratase deficiency and cancer: activation of hypoxia signaling? Cancer cell. 2007. PMID: 17418405
- Lehtonen HJ, Kiuru M, Ylisaukko-Oja SK. Increased risk of cancer in patients with fumarate hydratase germline mutation. Journal of medical genetics. 2006. PMID: 16155190
- Deschauer M, Gizatullina Z, Schulze A. Molecular and biochemical investigations in fumarase deficiency. Molecular genetics and metabolism. 2006. PMID: 16510303
- Badeloe S, van Geel M, van Steensel MA. Diffuse and segmental variants of cutaneous leiomyomatosis: novel mutations in the fumarate hydratase gene and review of the literature. Experimental dermatology. 2006. PMID: 16881969
- King A, Selak MA, Gottlieb E. Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer. Oncogene. 2006. PMID: 16892081
- Alam NA, Rowan AJ, Wortham NC. Genetic and functional analyses of FH mutations in multiple cutaneous and uterine leiomyomatosis, hereditary leiomyomatosis and renal cancer, and fumarate hydratase deficiency. Human molecular genetics. 2003. PMID: 12761039
- Zeman J, Krijt J, Stratilová L. Abnormalities in succinylpurines in fumarase deficiency: possible role in pathogenesis of CNS impairment. Journal of inherited metabolic disease. 2000. PMID: 10896297