ETHE1

Summary

ETHE1 (ETHE1 persulfide dioxygenase, HGNC:23287) is a protein-coding gene on chromosome 19q13.31, encoding Persulfide dioxygenase ETHE1, mitochondrial (O95571). Sulfur dioxygenase that plays an essential role in hydrogen sulfide catabolism in the mitochondrial matrix.

This gene encodes a member of the metallo beta-lactamase family of iron-containing proteins involved in the mitochondrial sulfide oxidation pathway. The encoded protein catalyzes the oxidation of a persulfide substrate to sulfite. Certain mutations in this gene cause ethylmalonic encephalopathy, an infantile metabolic disorder affecting the brain, gastrointestinal tract and peripheral vessels. Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 23474 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Leigh syndrome (Definitive, ClinGen) — +1 more curated relationship
• Clinical variants (ClinVar): 488 total — 44 pathogenic, 54 likely-pathogenic
• Phenotypes (HPO): 31
• MANE Select transcript: NM_014297

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23287
Approved symbol	ETHE1
Name	ETHE1 persulfide dioxygenase
Location	19q13.31
Locus type	gene with protein product
Status	Approved
Aliases	YF13H12, HSCO
Ensembl gene	ENSG00000105755
Ensembl biotype	protein_coding
OMIM	608451
Entrez	23474

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 12 protein_coding, 3 nonsense_mediated_decay, 1 retained_intron

ENST00000292147, ENST00000594342, ENST00000595115, ENST00000598330, ENST00000600651, ENST00000602138, ENST00000880121, ENST00000880122, ENST00000880123, ENST00000880124, ENST00000880125, ENST00000880126, ENST00000930538, ENST00000930539, ENST00000970449, ENST00000970450

RefSeq mRNA: 4 — MANE Select: NM_014297 NM_001320867, NM_001320868, NM_001320869, NM_014297

CCDS: CCDS12622

Canonical transcript exons

ENST00000292147 — 7 exons

Exon	Start	End
ENSE00001112388	43506719	43506902
ENSE00003083457	43527097	43527201
ENSE00003495773	43508775	43508864
ENSE00003565139	43526515	43526659
ENSE00003657367	43507944	43508060
ENSE00003658026	43526201	43526349
ENSE00003666457	43511437	43511566

Expression profiles

Bgee: expression breadth ubiquitous, 276 present calls, max score 99.69.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 36.2698 / max 379.6635, expressed in 1806 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
181283	29.7433	1798
181284	6.5265	1736

Top tissues by expression

292 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
mucosa of transverse colon	UBERON:0004991	99.69	gold quality
ileal mucosa	UBERON:0000331	99.20	gold quality
colonic mucosa	UBERON:0000317	98.89	gold quality
rectum	UBERON:0001052	98.80	gold quality
mucosa of sigmoid colon	UBERON:0004993	98.69	gold quality
transverse colon	UBERON:0001157	97.83	gold quality
lower esophagus mucosa	UBERON:0035834	97.58	gold quality
esophagus mucosa	UBERON:0002469	96.35	gold quality
large intestine	UBERON:0000059	96.14	gold quality
colon	UBERON:0001155	96.04	gold quality
small intestine Peyer’s patch	UBERON:0003454	95.71	gold quality
intestine	UBERON:0000160	95.64	gold quality
small intestine	UBERON:0002108	95.00	gold quality
stromal cell of endometrium	CL:0002255	94.91	gold quality
granulocyte	CL:0000094	94.87	gold quality
pharyngeal mucosa	UBERON:0000355	94.83	gold quality
duodenum	UBERON:0002114	94.78	gold quality
esophagus	UBERON:0001043	94.47	gold quality
sigmoid colon	UBERON:0001159	94.45	gold quality
minor salivary gland	UBERON:0001830	94.13	gold quality
body of stomach	UBERON:0001161	94.10	gold quality
mouth mucosa	UBERON:0003729	93.65	gold quality
right lobe of liver	UBERON:0001114	93.62	gold quality
epithelium of esophagus	UBERON:0001976	93.56	gold quality
muscle layer of sigmoid colon	UBERON:0035805	93.48	gold quality
type B pancreatic cell	CL:0000169	93.21	silver quality
esophagus squamous epithelium	UBERON:0006920	93.12	gold quality
saliva-secreting gland	UBERON:0001044	92.89	gold quality
monocyte	CL:0000576	92.76	gold quality
smooth muscle tissue	UBERON:0001135	92.74	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-HCAD-13	yes	468.03
E-MTAB-8410	yes	43.90
E-GEOD-125970	yes	20.93
E-ANND-3	yes	8.87
E-MTAB-7303	no	478.26

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

14 targeting ETHE1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-561-3P	99.64	70.90	3647
HSA-MIR-3153	99.55	67.59	2337
HSA-MIR-6080	99.43	69.43	373
HSA-MIR-633	98.35	69.45	1167
HSA-MIR-7113-5P	97.88	67.33	1735
HSA-MIR-1224-3P	97.24	65.92	851
HSA-MIR-6726-5P	95.97	63.72	841
HSA-MIR-920	95.97	63.95	811
HSA-MIR-4300	95.85	64.56	1003
HSA-MIR-5591-5P	95.85	64.76	1002
HSA-MIR-6786-5P	89.01	59.75	103

Literature-anchored findings (GeneRIF, showing 14)

• role of the ETHE1 gene product in mitochondrial homeostasis and energy metabolism (PMID:14732903)
• Mutations of ETHE1 were detected in all the typical ethylmalonic encephalopathy patients analysed, but no ETHE1 mutations were identified in patients presenting with early onset progressive encephalopathy with ethylmalonic aciduria. (PMID:16183799)
• structural comparison of human ETHE1 and At1g53580 from Arabidopsis thaliana (PMID:16929096)
• 14 patients with EE were investigated for mutations in the ETHE1 gene. Of the 14 patients, 5 were found to carry novel mutations. (PMID:18593870)
• ETHE1 is a mitochondrial sulfur dioxygenase involved in catabolism of sulfide that accumulates to toxic levels in ethylmalonic encephalopathy. (PMID:19136963)
• Case Report: metabolic disturbances in 15-month-old male presenting with typical ethylmalonic encephalopathy associated with a homozygous ETHE1 mutation. (PMID:20978941)
• T152I mutation of ETHE1 results in a 3-fold lower activity. (PMID:23144459)
• ETHE1 R163W/R163Q mutations are associated with Ethylmalonic encephalopathy. (PMID:25198162)
• observations indicate the severe impact of ETHE1 deficiency on cellular physiology and redox state (PMID:27074420)
• ETHE1 is a major enzyme regulating endogenous glutathione persulfide /GS-(S)n-H and that its activity is controlled by polysulfidation of the Cys247 residue. (PMID:27742479)
• The mitochondrial enzyme ETHE1 is a persulfide dioxygenase essential for cellular sulfide detoxification, and its deficiency causes the severe and complex inherited metabolic disorder ethylmalonic encephalopathy (EE). (PMID:30391543)
• ETHE1 and MOCS1 deficiencies: Disruption of mitochondrial bioenergetics, dynamics, redox homeostasis and endoplasmic reticulum-mitochondria crosstalk in patient fibroblasts. (PMID:31477743)
• Ethylmalonic encephalopathy 1 initiates overactive autophagy in depleted uranium-induced cytotoxicity in the human embryonic kidney 293 cells. (PMID:33274826)
• Ethylmalonic encephalopathy ETHE1 p. D165H mutation alters the mitochondrial function in human skeletal muscle proteome. (PMID:33639274)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ethe1	ENSDARG00000005713
mus_musculus	Ethe1	ENSMUSG00000064254
rattus_norvegicus	Ethe1	ENSRNOG00000019982
drosophila_melanogaster	CG30022	FBGN0050022
caenorhabditis_elegans		WBGENE00007886

Paralogs (4): HAGH (ENSG00000063854), HAGHL (ENSG00000103253), PNKD (ENSG00000127838), MBLAC2 (ENSG00000176055)

Protein

Protein identifiers

Persulfide dioxygenase ETHE1, mitochondrial — O95571 (reviewed: O95571)

Alternative names: Ethylmalonic encephalopathy protein 1, Hepatoma subtracted clone one protein, Sulfur dioxygenase ETHE1

All UniProt accessions (7): O95571, A0A0S2Z580, A0A0S2Z5B3, A0A0S2Z5N8, M0QX80, M0QXB5, M0QY80

UniProt curated annotations — full annotation on UniProt →

Function. 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.

Subunit / interactions. Homodimer. Monomer. Interacts with TST. May interact with RELA.

Subcellular location. Cytoplasm. Nucleus. Mitochondrion matrix.

Tissue specificity. Ubiquitously expressed.

Disease relevance. Ethylmalonic encephalopathy (EE) [MIM:602473] Autosomal recessive disorder characterized by neurodevelopmental delay and regression, recurrent petechiae, acrocyanosis, diarrhea, leading to death in the first decade of life. It is also associated with persistent lactic acidemia and ethylmalonic and methylsuccinic aciduria. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Glutathione increases enzyme activity.

Cofactor. Binds 1 Fe(2+) ion per subunit.

Similarity. Belongs to the metallo-beta-lactamase superfamily. Glyoxalase II family.

RefSeq proteins (4): NP_001307796, NP_001307797, NP_001307798, NP_055112* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001279	Metallo-B-lactamas	Domain
IPR036866	RibonucZ/Hydroxyglut_hydro	Homologous_superfamily
IPR044528	POD-like_MBL-fold	Domain
IPR051682	Mito_Persulfide_Diox	Family

Pfam: PF00753

Catalyzed reactions (Rhea), 1 shown:

• S-sulfanylglutathione + O2 + H2O = sulfite + glutathione + 2 H(+) (RHEA:12981)

UniProt features (47 total): strand 14, sequence variant 10, helix 8, turn 5, modified residue 5, binding site 3, transit peptide 1, chain 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
4CHL	X-RAY DIFFRACTION	2.61

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95571-F1	93.05	0.90

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (3): 79; 135; 154

Post-translational modifications (5): 14, 19, 66, 172, 172

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-1614517	Sulfide oxidation to sulfate

MSigDB gene sets: 249 (showing top): WWTAAGGC_UNKNOWN, BASSO_B_LYMPHOCYTE_NETWORK, HEIDENBLAD_AMPLICON_8Q24_DN, MARTINEZ_RB1_TARGETS_UP, UEDA_PERIFERAL_CLOCK, KOYAMA_SEMA3B_TARGETS_UP, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM4, GOBP_AMIDE_METABOLIC_PROCESS, WTGAAAT_UNKNOWN, LUI_THYROID_CANCER_CLUSTER_5, HAHTOLA_SEZARY_SYNDROM_UP, FREAC4_01, GOBP_GLUTATHIONE_METABOLIC_PROCESS, WENG_POR_TARGETS_GLOBAL_UP, GOBP_MODIFIED_AMINO_ACID_METABOLIC_PROCESS

GO Biological Process (2): glutathione metabolic process (GO:0006749), hydrogen sulfide metabolic process (GO:0070813)

GO Molecular Function (7): iron ion binding (GO:0005506), identical protein binding (GO:0042802), sulfur dioxygenase activity (GO:0050313), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), metal ion binding (GO:0046872), dioxygenase activity (GO:0051213)

GO Cellular Component (5): nucleoplasm (GO:0005654), cytoplasm (GO:0005737), mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), nucleus (GO:0005634)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Degradation of cysteine and homocysteine	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
sulfur compound metabolic process	2
cellular anatomical structure	2
intracellular membrane-bounded organelle	2
modified amino acid metabolic process	1
transition metal ion binding	1
protein binding	1
oxidoreductase activity, acting on single donors with incorporation of molecular oxygen, incorporation of two atoms of oxygen	1
binding	1
catalytic activity	1
cation binding	1
oxidoreductase activity	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
mitochondrion	1
intracellular organelle lumen	1

Protein interactions and networks

STRING

1512 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ETHE1	SQOR	Q9Y6N5	929
ETHE1	SUOX	P51687	853
ETHE1	TST	Q16762	808
ETHE1	LRPPRC	P42704	775
ETHE1	MPST	P25325	750
ETHE1	ACADS	P16219	697
ETHE1	ACADSB	P45954	689
ETHE1	CTH	P32929	669
ETHE1	PHLDB3	Q6NSJ2	646
ETHE1	P0DN79	P0DN79	636
ETHE1	H7C2H4	H7C2H4	635
ETHE1	CDO1	P78513	597
ETHE1	MOCS1	Q9NZB8	533
ETHE1	SHMT2	P34897	506
ETHE1	TSTD1	Q8NFU3	486
ETHE1	BCS1L	Q9Y276	486

IntAct

31 interactions, top by confidence:

A	B	Type	Score
NDUFS7	NDUFS8	psi-mi:“MI:0914”(association)	0.640
FGL1	LCMT2	psi-mi:“MI:0914”(association)	0.640
ETHE1	ETHE1	psi-mi:“MI:0915”(physical association)	0.560
ETHE1	TXN2	psi-mi:“MI:0915”(physical association)	0.560
ETHE1	ATG9A	psi-mi:“MI:0915”(physical association)	0.560
ETHE1	KRTAP19-2	psi-mi:“MI:0915”(physical association)	0.560
ETHE1	GORASP2	psi-mi:“MI:0915”(physical association)	0.560
	AGPS	psi-mi:“MI:0915”(physical association)	0.400
	TK2	psi-mi:“MI:0915”(physical association)	0.400
SIRT4	VWA8	psi-mi:“MI:0914”(association)	0.350
PRNP	CARNS1	psi-mi:“MI:0914”(association)	0.350
FGL1	DNM1L	psi-mi:“MI:0914”(association)	0.350
	AGPS	psi-mi:“MI:0914”(association)	0.350
FECH	POTEF	psi-mi:“MI:0914”(association)	0.350
HOOK3	ETHE1	psi-mi:“MI:0914”(association)	0.350
ETHE1	ETHE1	psi-mi:“MI:0915”(physical association)	0.000
TXN2	ETHE1	psi-mi:“MI:0915”(physical association)	0.000
ATG9A	ETHE1	psi-mi:“MI:0915”(physical association)	0.000
ETHE1	KRTAP19-2	psi-mi:“MI:0915”(physical association)	0.000
ETHE1	GORASP2	psi-mi:“MI:0915”(physical association)	0.000
ETHE1	ilvD	psi-mi:“MI:0915”(physical association)	0.000
ETHE1	RIF1	psi-mi:“MI:0915”(physical association)	0.000
ETHE1	IGSF21	psi-mi:“MI:0915”(physical association)	0.000
ETHE1	ATP6V1H	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (60): ETHE1 (Affinity Capture-MS), IDH1 (Co-fractionation), ETHE1 (Affinity Capture-MS), ETHE1 (Affinity Capture-MS), FH (Co-fractionation), GSTP1 (Co-fractionation), C21orf33 (Co-fractionation), EHHADH (Co-fractionation), PMPCA (Co-fractionation), FXN (Co-fractionation), CLIC4 (Co-fractionation), ACO2 (Co-fractionation), GRHPR (Co-fractionation), GLRX5 (Co-fractionation), TPI1 (Co-fractionation)

ESM2 similar proteins: A1A4L8, A2BDX3, A4RPM5, A5GFZ6, A6NK58, B4FAT0, B4NXF7, B6TNK6, O19179, O43323, O95396, O95571, P19971, P55203, P85971, Q02846, Q05922, Q08DH8, Q0VFH3, Q14BV6, Q17CA7, Q1WNP0, Q3KQV9, Q3TW96, Q3UQ84, Q561R2, Q58E95, Q5PQQ1, Q5ZKI2, Q61488, Q66JK4, Q6PAT0, Q7PY41, Q86U10, Q8AWD2, Q8NFV4, Q8VBZ0, Q8VDG5, Q923K4, Q96EY9

Diamond homologs: A0A7R7ZLL0, A0KIK2, A1S6T3, A3PBT3, A3PIB4, A4SPI6, A4WUN2, A5FZE9, A6WXE0, A9MPF3, B0RTE9, B0TXY0, C4LC58, O95571, P05446, Q0AM20, Q12BV7, Q13F06, Q2J429, Q2SJ47, Q31BX5, Q3J436, Q3JRV4, Q3T094, Q46Z82, Q47FN7, Q4URM1, Q57544, Q6ML19, Q6NC62, Q7N809, Q7NG34, Q87YS8, Q8PBY0, Q9C8L4, Q9DCM0, A5VSR1, A9IZW8, A9M8S2, B0CIU0

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

488 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	44
Likely pathogenic	54
Uncertain significance	97
Likely benign	228
Benign	26

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1361099	NM_014297.5(ETHE1):c.622G>T (p.Glu208Ter)	Pathogenic
1379077	NM_014297.5(ETHE1):c.413del (p.Gly138fs)	Pathogenic
1396975	NM_014297.5(ETHE1):c.325C>T (p.Gln109Ter)	Pathogenic
1412035	NM_014297.5(ETHE1):c.645_655del (p.Leu215_Thr216insTer)	Pathogenic
1452053	NM_014297.5(ETHE1):c.254_258dup (p.Gly87fs)	Pathogenic
1456400	NC_000019.9:g.(?44015579)(44031339_?)del	Pathogenic
1809751	NM_014297.5(ETHE1):c.576C>A (p.Tyr192Ter)	Pathogenic
1941827	NM_014297.5(ETHE1):c.43del (p.Gln15fs)	Pathogenic
2012369	NM_014297.5(ETHE1):c.448_469dup (p.Leu157fs)	Pathogenic
214322	NM_014297.5(ETHE1):c.488G>A (p.Arg163Gln)	Pathogenic
214323	NM_014297.5(ETHE1):c.221dup (p.Tyr74Ter)	Pathogenic
2152319	NM_014297.5(ETHE1):c.2T>A (p.Met1Lys)	Pathogenic
2317	NM_014297.5(ETHE1):c.487C>T (p.Arg163Trp)	Pathogenic
2318	NM_014297.5(ETHE1):c.3G>T (p.Met1Ile)	Pathogenic
2710594	NM_014297.5(ETHE1):c.401_402del (p.Gly134fs)	Pathogenic
2711088	NM_014297.5(ETHE1):c.463dup (p.Ala155fs)	Pathogenic
2734186	NM_014297.5(ETHE1):c.19_20dup (p.Val8fs)	Pathogenic
2749492	NM_014297.5(ETHE1):c.418_419del (p.Val140fs)	Pathogenic
2802892	NM_014297.5(ETHE1):c.129_132del (p.Arg43fs)	Pathogenic
2833401	NM_014297.5(ETHE1):c.1A>C (p.Met1Leu)	Pathogenic
2836024	NM_014297.5(ETHE1):c.241del (p.His81fs)	Pathogenic
2843998	NM_014297.5(ETHE1):c.61del (p.Ala21fs)	Pathogenic
2858077	NM_014297.5(ETHE1):c.252_253dup (p.Ile85fs)	Pathogenic
2971554	NM_014297.5(ETHE1):c.396_397insAC (p.Pro133fs)	Pathogenic
30725	NM_014297.5(ETHE1):c.554T>G (p.Leu185Arg)	Pathogenic
3248451	NC_000019.9:g.(?44015569)(44015738_?)del	Pathogenic
3248452	NC_000019.9:g.(?44030333)(44031420_?)del	Pathogenic
3248453	NC_000019.9:g.(?44011044)(44014899_?)del	Pathogenic
3339327	NC_000019.9:g.(44015719_44030352)(44031354?)del	Pathogenic
3600294	NM_014297.5(ETHE1):c.81+1del	Pathogenic

SpliceAI

959 predictions. Top by Δscore:

Variant	Effect	Δscore
19:43507940:TCACC:T	donor_loss	1.0000
19:43507941:CACCT:C	donor_loss	1.0000
19:43507942:A:AC	donor_gain	1.0000
19:43507943:C:A	donor_loss	1.0000
19:43507943:C:CC	donor_gain	1.0000
19:43507943:CCTAT:C	donor_gain	1.0000
19:43507947:T:C	donor_gain	1.0000
19:43508056:GAACC:G	acceptor_gain	1.0000
19:43508057:AACC:A	acceptor_gain	1.0000
19:43508058:ACC:A	acceptor_gain	1.0000
19:43508059:CC:C	acceptor_gain	1.0000
19:43508059:CCC:C	acceptor_gain	1.0000
19:43508060:CC:C	acceptor_gain	1.0000
19:43508061:C:CC	acceptor_gain	1.0000
19:43508061:C:T	acceptor_gain	1.0000
19:43508069:C:CT	acceptor_gain	1.0000
19:43508069:C:T	acceptor_gain	1.0000
19:43508070:A:T	acceptor_gain	1.0000
19:43508769:CCTCA:C	donor_loss	1.0000
19:43508770:CTCA:C	donor_loss	1.0000
19:43508771:TCA:T	donor_loss	1.0000
19:43508773:A:AC	donor_gain	1.0000
19:43508773:A:C	donor_loss	1.0000
19:43508774:C:CA	donor_loss	1.0000
19:43508774:C:CC	donor_gain	1.0000
19:43508860:ACAGC:A	acceptor_gain	1.0000
19:43508861:CAGC:C	acceptor_gain	1.0000
19:43508861:CAGCC:C	acceptor_gain	1.0000
19:43508862:AGC:A	acceptor_gain	1.0000
19:43508863:GC:G	acceptor_gain	1.0000

AlphaMissense

1644 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:43511481:T:A	D154V	0.997
19:43507990:A:C	F222L	0.995
19:43507990:A:T	F222L	0.995
19:43507992:A:G	F222L	0.995
19:43508787:G:C	H195D	0.995
19:43511537:G:C	H135Q	0.995
19:43511537:G:T	H135Q	0.995
19:43511490:A:G	F151S	0.994
19:43526327:G:C	D83E	0.994
19:43526327:G:T	D83E	0.994
19:43508020:G:C	N212K	0.993
19:43508020:G:T	N212K	0.993
19:43508785:G:C	H195Q	0.993
19:43508785:G:T	H195Q	0.993
19:43508837:A:T	V178D	0.993
19:43511484:C:A	G153V	0.993
19:43511546:G:C	S132R	0.993
19:43511546:G:T	S132R	0.993
19:43511548:T:G	S132R	0.993
19:43526328:T:A	D83V	0.993
19:43526345:A:C	N77K	0.993
19:43526345:A:T	N77K	0.993
19:43526599:C:G	A48P	0.993
19:43506883:G:C	N244K	0.992
19:43506883:G:T	N244K	0.992
19:43511480:A:C	D154E	0.992
19:43511480:A:T	D154E	0.992
19:43511481:T:G	D154A	0.992
19:43511539:G:C	H135D	0.992
19:43526324:G:C	H84Q	0.992

dbSNP variants (sampled 300 via entrez): RS1000029148 (19:43514121 G>A), RS1000093231 (19:43507682 A>C,G), RS1000241584 (19:43510571 G>A), RS1000243418 (19:43522569 C>T), RS1000285203 (19:43516754 T>G), RS1000844068 (19:43521259 A>G,T), RS1000865900 (19:43527321 C>A,G), RS1001049804 (19:43509775 G>A,T), RS1001135402 (19:43522784 T>C), RS1001169215 (19:43519155 G>A), RS1001186202 (19:43515601 G>A,C), RS1001237431 (19:43512282 A>G), RS1001270015 (19:43512621 G>T), RS1001369277 (19:43528523 AT>A,ATT), RS1001391836 (19:43525731 G>C)

Disease associations

OMIM: gene MIM:608451 | disease phenotypes: MIM:602473

GenCC curated gene-disease

Disease	Classification	Inheritance
Leigh syndrome	Definitive	Autosomal recessive
ethylmalonic encephalopathy	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Leigh syndrome	Definitive	AR

Mondo (3): ethylmalonic encephalopathy (MONDO:0011229), congenital nervous system disorder (MONDO:0002320), Leigh syndrome (MONDO:0009723)

Orphanet (1): Ethylmalonic encephalopathy (Orphanet:51188)

HPO phenotypes

31 total (30 of 31 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000967	Petechiae
HP:0001063	Acrocyanosis
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001290	Generalized hypotonia
HP:0001298	Encephalopathy
HP:0001508	Failure to thrive
HP:0001522	Death in infancy
HP:0002014	Diarrhea
HP:0002028	Chronic diarrhea
HP:0002071	Abnormality of extrapyramidal motor function
HP:0002376	Developmental regression
HP:0003128	Lactic acidosis
HP:0003219	Ethylmalonic aciduria
HP:0003487	Babinski sign
HP:0003593	Infantile onset
HP:0003688	Cytochrome C oxidase-negative muscle fibers
HP:0007183	Focal T2 hyperintense basal ganglia lesion
HP:0007256	Abnormal pyramidal sign
HP:0008046	Abnormal retinal vascular morphology
HP:0011968	Feeding difficulties
HP:0012747	Abnormal brainstem MRI signal intensity
HP:0012751	Abnormal basal ganglia MRI signal intensity
HP:0012758	Neurodevelopmental delay
HP:0012841	Retinal vascular tortuosity
HP:0033446	Elevated circulating butyrylcarnitine concentration

GWAS associations

0 associations (top):

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D007888	Leigh Disease	C10.228.140.163.100.412; C16.320.565.189.412; C16.320.565.202.810.444; C18.452.132.100.412; C18.452.648.189.412; C18.452.648.202.810.444; C18.452.660.520
C535737	Ethylmalonic encephalopathy (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

44 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	5
sodium arsenite	decreases expression, affects cotreatment, increases abundance	2
Arsenic Trioxide	decreases expression, decreases response to substance	2
Benzo(a)pyrene	decreases expression, increases methylation	2
Estradiol	affects expression, decreases expression	2
pirinixic acid	affects binding, decreases expression, increases activity	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, decreases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
beta-lapachone	increases expression	1
butyraldehyde	increases expression	1
perfluorooctanoic acid	increases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
potassium chromate(VI)	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
CGP 52608	affects binding, increases reaction	1
2-palmitoylglycerol	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
nutlin 3	affects cotreatment, increases secretion	1
bisphenol B	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
jinfukang	affects cotreatment, increases expression	1
(+)-JQ1 compound	increases expression	1
Acetaminophen	affects expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1
Atrazine	decreases expression	1
Cisplatin	affects cotreatment, increases expression	1
Dactinomycin	affects cotreatment, increases secretion	1
Doxorubicin	decreases expression	1

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D9WG	Ubigene HT-29 ETHE1 KO	Cancer cell line	Female
CVCL_E1WK	HAP1 ETHE1 (-) 2	Cancer cell line	Male
CVCL_XN56	HAP1 ETHE1 (-) 1	Cancer cell line	Male

Clinical trials (associated diseases)

15 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT01721733	PHASE2	COMPLETED	Safety and Efficacy Study of EPI-743 in Children With Leigh Syndrome
NCT02352896	PHASE2	COMPLETED	Long-Term Safety and Efficacy Evaluation of EPI-743 in Children With Leigh Syndrome
NCT03747328	PHASE2	WITHDRAWN	ABI-009 (Nab-sirolimus) in Patients With Genetically-confirmed Leigh or Leigh-like Syndrome
NCT06843811	PHASE2	ENROLLING_BY_INVITATION	Sirolimus for Leigh Syndrome
NCT06990984	PHASE2	NOT_YET_RECRUITING	A Dose-ranging Study of TTI-0102 in Adults and Children With Leigh Syndrome Spectrum (LSS)
NCT02544217	PHASE1	COMPLETED	A Dose-escalating Clinical Trial With KH176
NCT04378075	PHASE2/PHASE3	TERMINATED	A Study to Evaluate Efficacy and Safety of Vatiquinone for Treating Mitochondrial Disease in Participants With Refractory Epilepsy
NCT01780168	Not specified	RECRUITING	The NIH MINI Study: Metabolism, Infection, and Immunity in Inborn Errors of Metabolism
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT01803906	Not specified	ENROLLING_BY_INVITATION	Tissue Sample Study for Mitochondrial Disorders
NCT03137355	Not specified	RECRUITING	The International Registry for Leigh Syndrome
NCT05277363	Not specified	WITHDRAWN	A Study of the Natural Course of SURF1 Deficiency
NCT05554835	Not specified	RECRUITING	Global Registry and Natural History Study for Mitochondrial Disorders
NCT06967831	Not specified	RECRUITING	Drug Repurposing for Mitochondrial Disorders Using iPSCs Derived Neural Cells
NCT00728481	PHASE2/PHASE3	COMPLETED	The Role Of Gastroesophageal Reflux Disease (GERD) in Eosinophilic Esophagitis