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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. ETHE1 is a gene that codes for an enzyme called ETHE1 persulfide dioxygenase, which is active in the mitochondria of cells.
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, also known as ETHE1 persulfide dioxygenase, plays a critical role in cellular metabolism, particularly within the mitochondria. Mitochondria are often referred to as the 'powerhouses' of the cell, responsible for generating energy. The ETHE1 enzyme is involved in the detoxification pathway of hydrogen sulfide (H2S), a molecule that is naturally produced in the body and by gut bacteria.
While low levels of sulfide are necessary for normal cellular processes, elevated concentrations can be toxic. The ETHE1 enzyme's function is to convert sulfide into less harmful compounds, thereby preventing its accumulation and protecting mitochondrial function. Genetic changes in ETHE1 can impair this process, leading to a build-up of toxic sulfide.
What the gene does
The ETHE1 gene provides the blueprint for an enzyme that functions primarily in the mitochondria, the organelles responsible for cellular respiration and energy production. This enzyme, ETHE1 persulfide dioxygenase, is a key component of the sulfide detoxification pathway. Sulfide is a by-product of normal metabolic processes and is also generated by bacteria residing in the gastrointestinal tract.
Although sulfide is crucial for various cellular activities at low concentrations, it becomes highly toxic when its levels increase. Excess sulfide can disrupt mitochondrial energy production, specifically by inhibiting cytochrome c oxidase (COX), a critical enzyme complex in the electron transport chain. The ETHE1 enzyme converts sulfide into sulphate, effectively neutralising its harmful effects and safeguarding mitochondrial function 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 its precise address on the long arm ('q') of chromosome 19.
Protein structure
The ETHE1 protein consists of 254 amino acids. Domain architecture has not been experimentally characterised in detail for this protein.
Key variants
Variants in the ETHE1 gene can alter the protein's ability to effectively break down sulfide. Over 30 different genetic changes have been identified in individuals with specific health conditions associated with ETHE1 dysfunction. These variants can lead to a range of clinical presentations, depending on how severely they impair the enzyme's function.
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 within the ETHE1 gene are primarily associated with a severe inherited condition called ethylmalonic encephalopathy. This rare disorder affects multiple body systems, including the nervous system, blood vessels, and intestines. Individuals with this condition often experience developmental delay, movement disorders, skin rashes, and discoloration of the hands and feet. In some cases, ETHE1 variants have also been linked to Leigh syndrome.
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 within the NHS Genomic Medicine Service, with several of its associated conditions listed on various PanelApp green panels. These 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', indicating its relevance in diagnosing these conditions.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does the ETHE1 gene do?
The ETHE1 gene provides instructions for an enzyme in the mitochondria that is responsible for breaking down sulfide. This process is crucial for preventing toxic levels of sulfide from building up in the body and for maintaining normal cellular energy production.
What happens if there are changes in the ETHE1 gene?
Changes, or variants, in the ETHE1 gene can lead to reduced or absent enzyme function, causing sulfide to accumulate to toxic levels. This can result in conditions such as ethylmalonic encephalopathy, which affects various body systems including the nervous system.
Is ethylmalonic encephalopathy an inherited condition?
Yes, ethylmalonic encephalopathy is an inherited condition typically passed down in an autosomal recessive manner. This means that an individual must inherit two copies of the altered ETHE1 gene (one from each parent) to develop 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