ETHE1

Chr 19AR

ETHE1 persulfide dioxygenase

NCBI Gene: 23474ENSG00000105755UniProt: O95571

Sulfur dioxygenase that plays an essential role in hydrogen sulfide catabolism in the mitochondrial matrix. Hydrogen sulfide (H(2)S) is first oxidized by SQRDL, giving rise to cysteine persulfide residues. ETHE1 consumes molecular oxygen to catalyze the oxidation of the persulfide, once it has been transferred to a thiophilic acceptor, such as glutathione (R-SSH). Plays an important role in metabolic homeostasis in mitochondria by metabolizing hydrogen sulfide and preventing the accumulation of supraphysiological H(2)S levels that have toxic effects, due to the inhibition of cytochrome c oxidase. First described as a protein that can shuttle between the nucleus and the cytoplasm and suppress p53-induced apoptosis by sequestering the transcription factor RELA/NFKB3 in the cytoplasm and preventing its accumulation in the nucleus (PubMed:12398897)

Primary Disease Associations & Inheritance

Ethylmalonic encephalopathyMIM #602473
AR
491
ClinVar variants
61
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— ETHE1
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
61 Pathogenic / Likely Pathogenic· 72 VUS of 491 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
1.46LOEUF
pLI 0.000
Z-score 0.49
OE 0.84 (0.50–1.46)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.96Z-score
OE missense 0.77 (0.66–0.91)
110 obs / 142.1 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.84 (0.50–1.46)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.77 (0.66–0.91)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.93
0≤1.21.6
LoF obs/exp: 9 / 10.7Missense obs/exp: 110 / 142.1Syn Z: 0.45

ClinVar Variant Classifications

491 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic27
Likely Pathogenic34
VUS72
Likely Benign156
Benign1
Conflicting1
27
Pathogenic
34
Likely Pathogenic
72
VUS
156
Likely Benign
1
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
17
2
8
0
27
Likely Pathogenic
24
5
5
0
34
VUS
0
55
12
5
72
Likely Benign
1
1
69
85
156
Benign
0
0
1
0
1
Conflicting
—1
Total42639590291

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

ETHE1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

ETHE1-related ethylmalonic encephalopathy

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Ethylmalonic encephalopathy

MIM #602473

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
ETHE1 dampens colorectal cancer angiogenesis by promoting TC45 Dephosphorylation of STAT3 to inhibit VEGF-A expression.
She X et al.·Cell Death Dis
2024
Emerging roles of hydrogen sulfide-metabolizing enzymes in cancer.
Dawoud A et al.·Redox Rep
2024Review
An atypically mild case of ethylmalonic encephalopathy with pathogenic ETHE1 variant.
Kashima DT et al.·Am J Med Genet A
2023Case report
Deficiency of the mitochondrial sulfide regulator ETHE1 disturbs cell growth, glutathione level and causes proteome alterations outside mitochondria.
Sahebekhtiari N et al.·Biochim Biophys Acta Mol Basis Dis
2019
Hydrogen sulfide as an anti-calcification stratagem in human aortic valve: Altered biogenesis and mitochondrial metabolism of H(2)S lead to H(2)S deficiency in calcific aortic valve disease.
Combi Z et al.·Redox Biol
2023
Mitochondrial diseases caused by toxic compound accumulation: from etiopathology to therapeutic approaches.
Di Meo I et al.·EMBO Mol Med
2015Review
Identification of a novel homozygous nonsense variant in a Chinese patient with ethylmalonic encephalopathy and a genotype-phenotype spectrum review.
Tao Y et al.·Clin Chim Acta
2020Review
Chronic exposure to sulfide causes accelerated degradation of cytochrome c oxidase in ethylmalonic encephalopathy.
Di Meo I et al.·Antioxid Redox Signal
2011
Ethylmalonic encephalopathy-report of two cases.
Heberle LC et al.·Brain Dev
2006Case report
Mechanism-based inhibition of human persulfide dioxygenase by γ-glutamyl-homocysteinyl-glycine.
Kabil O et al.·J Biol Chem
2018Functional
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools