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ETHE1
ETHE1 persulfide dioxygenase
The ETHE1 gene provides instructions for an enzyme crucial for breaking down sulfide within mitochondria, playing a vital role in cellular energy production and preventing toxicity. The ETHE1 gene encodes an enzyme called ETHE1 persulfide dioxygenase, which is primarily active within the mitochondria, the cell's powerhouses.
ETHE1 is located on the long (q) arm of chromosome 19, at band 19q13.31. Arm ratio per GRCh38 - banding schematic.
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Overview
The ETHE1 gene, fully known as ETHE1 persulfide dioxygenase, is responsible for producing a mitochondrial enzyme. This enzyme plays a critical role in the metabolic pathway that breaks down sulfide (H2S), a molecule naturally produced in the body and by gut bacteria.
While sulfide is necessary at low concentrations for normal cellular functions, its accumulation to high levels can be harmful. The ETHE1 enzyme's activity is therefore essential for maintaining healthy cellular environments, especially within the mitochondria, where it contributes to energy production and prevents cellular damage.
What the gene does
The ETHE1 enzyme is primarily active in the mitochondria, the organelles responsible for generating most of the chemical energy needed to power a cell's biochemical reactions. Its main function is to participate in the breakdown of sulfide, a molecule that can be toxic if it builds up. Sulfide is a byproduct of normal metabolic processes within the body's tissues and is also released by bacteria in the gastrointestinal system.
At physiological levels, sulfide is important for various cellular functions. However, when sulfide levels become elevated, it can disrupt numerous cellular activities. For instance, excess sulfide can inhibit cytochrome C oxidase (COX), an enzyme complex crucial for the final steps of energy production in mitochondria. The ETHE1 enzyme helps prevent this inhibition by converting toxic sulfide into less harmful compounds, thereby ensuring efficient mitochondrial energy production and overall cellular health.
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Chromosome location
The ETHE1 gene is located on chromosome 19, specifically at position 19q13.31. This designation indicates that the gene resides on the long (q) arm of chromosome 19, within region 13 and sub-band 31.
Protein structure
The ETHE1 protein consists of 254 amino acids. Domain architecture has not been experimentally characterised in detail for this protein.
Key variants
Genetic variations, or variants, in the ETHE1 gene can alter the function of the ETHE1 enzyme. These changes can reduce the enzyme's ability to process sulfide effectively, leading to its accumulation in cells and tissues. Such variants are typically inherited in an autosomal recessive manner, meaning a person must inherit two copies of a pathogenic variant (one from each parent) to be affected by an associated condition.
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.487C>T | p.Arg163Trp | Pathogenic | ★★★☆ | Ethylmalonic encephalopathy |
c.488G>A | p.Arg163Gln | Pathogenic | ★★★☆ | Ethylmalonic encephalopathy |
c.505+1G>A | - | Pathogenic | ★★★☆ | Ethylmalonic encephalopathy |
c.505+1G>T | - | Pathogenic | ★★★☆ | Ethylmalonic encephalopathy |
c.604dup | p.Val202fs | Pathogenic | ★★★☆ | Ethylmalonic encephalopathy |
c.189del | p.Gln63fs | Pathogenic/Likely pathogenic | ★★☆☆ | Ethylmalonic encephalopathy |
c.388del | p.Arg130fs | Pathogenic/Likely pathogenic | ★★☆☆ | Ethylmalonic encephalopathy |
c.43C>T | p.Gln15Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Ethylmalonic encephalopathy |
c.596-1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Ethylmalonic encephalopathy |
c.702_703del | p.Gln235fs | Pathogenic/Likely pathogenic | ★★☆☆ | Ethylmalonic encephalopathy |
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 ETHE1 gene are primarily associated with ethylmalonic encephalopathy. This rare, severe condition affects multiple body systems, including the nervous system, blood vessels, and intestines. Symptoms can include developmental delay, unusual movements, skin rashes characterised by small red spots (petechiae), and blue discolouration of the hands and feet (acrocyanosis).
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic ETHE1 variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
The ETHE1 gene is recognised in the UK's National Health Service (NHS) Genomic Medicine Service pathways. It is listed as 'green' on several NHS Genomic England PanelApp panels, indicating strong evidence for its association with human disease. These panels include DDG2P, Early onset or syndromic epilepsy, Intellectual disability, Likely inborn error of metabolism (R98), Mitochondrial disorders, Possible mitochondrial disorder, nuclear genes (R63), Structural basal ganglia disorders, and Undiagnosed metabolic disorders.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary role of the ETHE1 gene?
The ETHE1 gene provides instructions for making an enzyme that is crucial for detoxifying sulfide within the mitochondria. This enzyme helps break down sulfide, preventing its accumulation to toxic levels that could interfere with cellular energy production.
What happens if the ETHE1 gene is not working correctly?
If the ETHE1 gene is not functioning properly, it can lead to an accumulation of sulfide in the body. High levels of sulfide are toxic to cells, particularly in the mitochondria, which can disrupt energy production and cause damage to various tissues and organs, leading to conditions like ethylmalonic encephalopathy.
How is ethylmalonic encephalopathy inherited?
Ethylmalonic encephalopathy caused by ETHE1 variants is inherited in an autosomal recessive manner. This means an individual must inherit two copies of a pathogenic ETHE1 variant, one from each parent, to develop the condition. Parents who each carry one copy of the variant are typically unaffected themselves but have a 25% chance with each pregnancy of having a child with the condition.
References
- Pettinati I, Brem J, McDonough MA. Crystal structure of human persulfide dioxygenase: structural basis of ethylmalonic encephalopathy. Human molecular genetics. 2015. PMID: 25596185
- Tiranti V, Zeviani M. Altered sulfide (H(2)S) metabolism in ethylmalonic encephalopathy. Cold Spring Harbor perspectives in biology. 2013. PMID: 23284046
- Di Meo I, Fagiolari G, Prelle A. Chronic exposure to sulfide causes accelerated degradation of cytochrome c oxidase in ethylmalonic encephalopathy. Antioxidants & redox signaling. 2011. PMID: 20812865
- Tiranti V, Viscomi C, Hildebrandt T. Loss of ETHE1, a mitochondrial dioxygenase, causes fatal sulfide toxicity in ethylmalonic encephalopathy. Nature medicine. 2009. PMID: 19136963
- Tiranti V, Briem E, Lamantea E. ETHE1 mutations are specific to ethylmalonic encephalopathy. Journal of medical genetics. 2006. PMID: 16183799
- Tiranti V, D'Adamo P, Briem E. Ethylmalonic encephalopathy is caused by mutations in ETHE1, a gene encoding a mitochondrial matrix protein. American journal of human genetics. 2004. PMID: 14732903