ALOXE3

Summary

ALOXE3 (arachidonate epidermal lipoxygenase 3, HGNC:13743) is a protein-coding gene on chromosome 17p13.1, encoding Hydroperoxide isomerase ALOXE3 (Q9BYJ1). Non-heme iron-containing lipoxygenase which is atypical in that it displays a prominent hydroperoxide isomerase activity and a reduced lipoxygenases activity.

This gene is a member of the lipoxygenase family, which are catabolized by arachidonic acid-derived compounds. The encoded enzyme is a hydroperoxide isomerase that synthesizes a unique type of epoxy alcohol (8R-hydroxy-11R,12R-epoxyeicosa-5Z,9E,14Z-trienoic acid) from 12R-hydroperoxyeicosatetraenoic acid (12R-HPETE). This epoxy alcohol can activate the the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha), which is implicated in epidermal differentiation. Loss of function of the enzyme encoded by this gene results in ichthyosis, implicating the function of this gene in the differentiation of human skin. This gene is part of a cluster of lipoxygenase genes on 17p13.1. Mutations in this gene result in nonbullous congenital ichthyosiform erythroderma (NCIE). Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 59344 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autosomal recessive congenital ichthyosis 3 (Definitive, GenCC) — +3 more curated relationships
• Clinical variants (ClinVar): 362 total — 48 pathogenic, 21 likely-pathogenic
• Phenotypes (HPO): 49
• MANE Select transcript: NM_021628

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13743
Approved symbol	ALOXE3
Name	arachidonate epidermal lipoxygenase 3
Location	17p13.1
Locus type	gene with protein product
Status	Approved
Aliases	eLOX3, E-LOX
Ensembl gene	ENSG00000179148
Ensembl biotype	protein_coding
OMIM	607206
Entrez	59344

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 4 protein_coding, 2 nonsense_mediated_decay, 1 retained_intron

ENST00000318227, ENST00000380149, ENST00000448843, ENST00000583808, ENST00000714143, ENST00000714144, ENST00000714145

RefSeq mRNA: 3 — MANE Select: NM_021628 NM_001165960, NM_001369446, NM_021628

CCDS: CCDS11130

Canonical transcript exons

ENST00000448843 — 16 exons

Exon	Start	End
ENSE00001238446	8103323	8103493
ENSE00001238458	8104115	8104215
ENSE00001238466	8108468	8108589
ENSE00001238474	8109174	8109343
ENSE00001238484	8109916	8110002
ENSE00001238492	8110092	8110295
ENSE00001238503	8110385	8110528
ENSE00001238514	8111359	8111531
ENSE00001238522	8112093	8112196
ENSE00001238533	8114484	8114609
ENSE00001238541	8114938	8115057
ENSE00001238549	8115607	8115688
ENSE00001238556	8116776	8116980
ENSE00001351939	8095900	8096806
ENSE00001741152	8118486	8118514
ENSE00003468783	8117844	8118303

Expression profiles

Bgee: expression breadth ubiquitous, 141 present calls, max score 94.87.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.1475 / max 13.4519, expressed in 73 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
164358	0.1144	63
164360	0.0225	6
164359	0.0107	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
skin of leg	UBERON:0001511	94.87	gold quality
skin of abdomen	UBERON:0001416	93.36	gold quality
zone of skin	UBERON:0000014	90.75	gold quality
secondary oocyte	CL:0000655	85.84	silver quality
upper arm skin	UBERON:0004263	83.66	gold quality
upper leg skin	UBERON:0004262	82.90	gold quality
oocyte	CL:0000023	82.67	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.52	gold quality
tibialis anterior	UBERON:0001385	75.12	silver quality
tongue squamous epithelium	UBERON:0006919	73.11	gold quality
diaphragm	UBERON:0001103	72.59	gold quality
nipple	UBERON:0002030	71.98	silver quality
cerebellar hemisphere	UBERON:0002245	70.84	gold quality
right hemisphere of cerebellum	UBERON:0014890	70.82	gold quality
cerebellar cortex	UBERON:0002129	70.73	gold quality
penis	UBERON:0000989	69.93	gold quality
skin of hip	UBERON:0001554	69.02	gold quality
cerebellum	UBERON:0002037	68.69	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	68.55	gold quality
lower esophagus mucosa	UBERON:0035834	68.37	gold quality
mammalian vulva	UBERON:0000997	66.99	silver quality
cortical plate	UBERON:0005343	66.73	gold quality
pancreatic ductal cell	CL:0002079	65.45	silver quality
right frontal lobe	UBERON:0002810	64.89	gold quality
gingival epithelium	UBERON:0001949	63.12	silver quality
esophagus mucosa	UBERON:0002469	62.01	gold quality
deltoid	UBERON:0001476	60.15	gold quality
Brodmann (1909) area 9	UBERON:0013540	59.79	gold quality
prefrontal cortex	UBERON:0000451	59.54	gold quality
anterior cingulate cortex	UBERON:0009835	58.77	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.43

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): PPARG

miRNA regulators (miRDB)

54 targeting ALOXE3, 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-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-7845-5P	99.88	64.88	771
HSA-MIR-6857-5P	99.87	65.32	985
HSA-MIR-3151-5P	99.86	63.83	1069
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-3180-5P	99.82	69.12	2422
HSA-MIR-3150A-3P	99.76	64.44	1640
HSA-MIR-6763-5P	99.76	64.68	1767
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-298	99.63	67.56	1916
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-7106-5P	99.53	67.47	3574
HSA-MIR-4437	99.52	65.29	1266
HSA-MIR-12131	99.48	68.72	1673
HSA-MIR-520A-5P	99.35	66.72	1632
HSA-MIR-525-5P	99.35	66.85	1615
HSA-MIR-3925-5P	99.21	67.90	1466
HSA-MIR-4434	99.10	67.01	1984
HSA-MIR-5703	99.10	67.09	2053

Literature-anchored findings (GeneRIF, showing 20)

• Lipoxygenase-3 (ALOXE3) and 12(R)-lipoxygenase (ALOX12B) are mutated in non-bullous congenital ichthyosiform erythroderma (NCIE) linked to chromosome 17p13.1. (PMID:11773004)
• eLOX-3 hydrolase functions in the normal process of skin differentiation, and that the loss of function mutations are the basis of the LOX-dependent form of Non-bullous congenital ichthyosiform erythroderma. (PMID:15629692)
• The substrate preference of mouse eLOX3 and the unique occurrence of an 8S-LOX enzyme in mouse skin point to a potential LOX pathway for the production of epoxyalcohol in murine epidermal differentiation. (PMID:17045234)
• Formation of a ligand for the nuclear receptor PPARalpha may be one possibility by which 12R-LOX and eLOX3 contribute to epidermal differentiation. (PMID:17436029)
• mutation hotspots in ALOXE3 and allelic heterogeneity in ALOX12B may have roles in autosomal recessive congenital ichthyosis (PMID:19131948)
• ALOX12B mutations are the leading cause of self-improving collodion ichthyosis in Scandinavia, followed by ALOXE3 mutations, and TGM1 mutations (PMID:19890349)
• Dioxygenase activity of epidermal lipoxygenase-3 unveiled: typical and atypical features of its catalytic activity with natural and synthetic polyunsaturated fatty acids. (PMID:20921226)
• On the role of molecular oxygen in lipoxygenase activation: comparison and contrast of epidermal lipoxygenase-3 with soybean lipoxygenase-1. (PMID:20923767)
• Autosomal recessive congenital ichthyosis patients with NIPAL4 mutations and abnormal ichthyin expression showed increased 12R-LOX and eLOX-3 staining and a colocalization signal of these LOXs that was three times the normal intensity. (PMID:22622417)
• Loss-of-function mutations in the LOX genes ALOX12B and ALOXE3 have been found to represent the second most common cause of autosomal recessive congenital ichthyosis. [review] (PMID:23954555)
• This review covers the background to discovery of the two key lipoxygenases (LOX) involved in epidermal barrier function, 12R-LOX and eLOX3. [review] (PMID:24021977)
• Case Report: homozygous ALOXE3 mutation causing autosomal recessive congenital ichthyosis. (PMID:25423909)
• In summary, we have identified three novel sequence variants, one in TGM1 and two in ALOXE3, in three consanguineous families segregating lamellar ichthyosis and congenital ichthyosiform erythroderma types of autosomal recessive congenital ichthyosis. (PMID:26578203)
• Case Report: ALOXE3 mutation causing congenital ichthyosis and recurrent eczema. (PMID:27868147)
• Identification and association of recurrent ALOXE3 mutation with non-bullous congenital ichthyosiform erythroderma in two ethnically distinct Pakistani families has been reported. (PMID:29935003)
• Study found that DNA methylation at cg25365794 in ALOXE3 gene is associated with urinary 8-isoprostane levels and with specific cancer outcomes. Whoever, the association between urinary 8-isoprostane levels and DNA methylation at the ALOXE3 gene may not be causal. (PMID:30678711)
• Variants in NIPAL4 and ALOXE3 cause autosomal recessive congenital ichthyosis in Pakistani families. (PMID:31883158)
• Phenotypic suppression of acral peeling skin syndrome in a patient with autosomal recessive congenital ichthyosis. (PMID:32618001)
• Meta-Analysis of Mutations in ALOX12B or ALOXE3 Identified in a Large Cohort of 224 Patients. (PMID:33435499)
• The ALOXE3 gene variants from patients with Dravet syndrome decrease gene expression and enzyme activity. (PMID:33581311)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	si:dkey-17e16.9	ENSDARG00000073781
mus_musculus	Aloxe3	ENSMUSG00000020892
rattus_norvegicus	Aloxe3	ENSRNOG00000007454

Paralogs (5): ALOX5 (ENSG00000012779), ALOX12 (ENSG00000108839), ALOX15 (ENSG00000161905), ALOX12B (ENSG00000179477), ALOX15B (ENSG00000179593)

Protein

Protein identifiers

Hydroperoxide isomerase ALOXE3 — Q9BYJ1 (reviewed: Q9BYJ1)

Alternative names: Epidermis-type lipoxygenase 3, Hydroperoxy dehydratase ALOXE3, Hydroperoxy icosatetraenoate dehydratase, Hydroperoxy icosatetraenoate isomerase

All UniProt accessions (5): Q9BYJ1, A0AAQ5BHG0, A0AAQ5BHH1, A0AAQ5BHK9, J3KPH2

UniProt curated annotations — full annotation on UniProt →

Function. Non-heme iron-containing lipoxygenase which is atypical in that it displays a prominent hydroperoxide isomerase activity and a reduced lipoxygenases activity. The hydroperoxide isomerase activity catalyzes the isomerization of hydroperoxides, derived from arachidonic and linoleic acid by ALOX12B, into hepoxilin-type epoxyalcohols and ketones. In presence of oxygen, oxygenates polyunsaturated fatty acids, including arachidonic acid, to produce fatty acid hydroperoxides. In the skin, acts downstream of ALOX12B on the linoleate moiety of esterified omega-hydroxyacyl-sphingosine (EOS) ceramides to produce an epoxy-ketone derivative, a crucial step in the conjugation of omega-hydroxyceramide to membrane proteins. Therefore plays a crucial role in the synthesis of corneocytes lipid envelope and the establishment of the skin barrier to water loss. In parallel, it may have a signaling function in barrier formation through the production of hepoxilins metabolites. Also plays a role in adipocyte differentiation through hepoxilin A3 and hepoxilin B3 production which in turn activate PPARG. Through the production of hepoxilins in the spinal cord, it may regulate inflammatory tactile allodynia.

Subcellular location. Cytoplasm.

Tissue specificity. Predominantly expressed in skin.

Disease relevance. Ichthyosis, congenital, autosomal recessive 3 (ARCI3) [MIM:606545] A form of autosomal recessive congenital ichthyosis, a disorder of keratinization with abnormal differentiation and desquamation of the epidermis, resulting in abnormal skin scaling over the whole body. The main skin phenotypes are lamellar ichthyosis (LI) and non-bullous congenital ichthyosiform erythroderma (NCIE), although phenotypic overlap within the same patient or among patients from the same family can occur. Lamellar ichthyosis is a condition often associated with an embedment in a collodion-like membrane at birth; skin scales later develop, covering the entire body surface. Non-bullous congenital ichthyosiform erythroderma characterized by fine whitish scaling on an erythrodermal background; larger brownish scales are present on the buttocks, neck and legs. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Lipoxygenase activity is activated by 13(S)-HPODE leading to an active free ferric enzyme. The lipoxygenase and hydroperoxide isomerase activities are in competition and are reciprocally regulated by oxygen. The oxygen reacts with an epoxyallylic radical intermediate leading to an epoxyallylic peroxyl radical, which, due to its limited reactivity within the enzyme active site, it dissociates and leaves the enzyme in the activated free ferric state.

Cofactor. Binds 1 Fe cation per subunit.

Pathway. Lipid metabolism; hydroperoxy eicosatetraenoic acid biosynthesis. Lipid metabolism; sphingolipid metabolism.

Similarity. Belongs to the lipoxygenase family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9BYJ1-1	1	yes
Q9BYJ1-2	2

RefSeq proteins (3): NP_001159432, NP_001356375, NP_067641* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000907	LipOase	Family
IPR001024	PLAT/LH2_dom	Domain
IPR001885	LipOase_mml	Family
IPR013819	LipOase_C	Domain
IPR020833	LipOase_Fe_BS	Binding_site
IPR020834	LipOase_CS	Conserved_site
IPR036226	LipOase_C_sf	Homologous_superfamily
IPR036392	PLAT/LH2_dom_sf	Homologous_superfamily
IPR042062	PLAT_LOX_verte	Domain

Pfam: PF00305, PF01477

Enzyme classification (BRENDA):

• EC 4.2.1.152 — hydroperoxy icosatetraenoate dehydratase (BRENDA: 2 organisms, 18 substrates, 1 inhibitors, 0 Km, 0 kcat entries)

Catalyzed reactions (Rhea), 12 shown:

• (8S)-hydroperoxy-(5Z,9E,11Z,14Z)-eicosatetraenoate = 8-oxo-(5Z,9E,11Z,14Z)-eicosatetraenoate + H2O (RHEA:37927)
• (8S)-hydroperoxy-(5Z,9E,11Z,14Z)-eicosatetraenoate = (10R)-hydroxy-(8S,9S)-epoxy-(5Z,11Z,14Z)-eicosatrienoate (RHEA:37931)
• (8R)-hydroperoxy-(5Z,9E,11Z,14Z)-eicosatetraenoate = 8-oxo-(5Z,9E,11Z,14Z)-eicosatetraenoate + H2O (RHEA:37935)
• (12R)-hydroperoxy-(5Z,8Z,10E,14Z)-eicosatetraenoate = (8R)-hydroxy-(11R,12R)-epoxy-(5Z,9E,14Z)-eicosatrienoate (RHEA:37939)
• (12R)-hydroperoxy-(5Z,8Z,10E,14Z)-eicosatetraenoate = 12-oxo-(5Z,8Z,10E,14Z)-eicosatetraenoate + H2O (RHEA:37943)
• (12S)-hydroperoxy-(5Z,8Z,10E,14Z)-eicosatetraenoate = 12-oxo-(5Z,8Z,10E,14Z)-eicosatetraenoate + H2O (RHEA:37947)
• (12S)-hydroperoxy-(5Z,8Z,10E,14Z)-eicosatetraenoate = (10R)-hydroxy-(11S,12S)-epoxy-(5Z,8Z,14Z)-eicosatrienoate (RHEA:37951)
• (12S)-hydroperoxy-(5Z,8Z,10E,14Z)-eicosatetraenoate = (8R)-hydroxy-(11S,12S)-epoxy-(5Z,9E,14Z)-eicosatrienoate (RHEA:37955)
• (15S)-hydroperoxy-(5Z,8Z,11Z,13E)-eicosatetraenoate = (13R)-hydroxy-(14S,15S)-epoxy-(5Z,8Z,11Z)-eicosatrienoate (RHEA:37959)
• N-[omega-(9R)-hydroperoxy-(10E,12Z)-octadecadienoyloxy]acyl-beta-D-glucosyl-(1<->1)-octadecasphing-4E-enine = a N-[omega-(9R,10R)-epoxy-(13R)-hydroxy-(11E)-octadecenoyloxy]acyl-beta-D-glucosyl-(1<->1)-sphing-4E-enine (RHEA:40503)
• a N-[omega-(9R)-hydroperoxy-(10E,12Z)-octadecadienoyloxy]-acylsphin-4E-enine = a N-[omega-(9R,10R)-epoxy-(13R)-hydroxy-(11E)-octadecenoyloxy]-acylsphing-4E-enine (RHEA:41243)
• (5S)-hydroperoxy-(6E,8Z,11Z,14Z)-eicosatetraenoate = 7R-hydroxy-5S,6S-epoxy-(8Z,11Z,14Z)-eicosatrienoate (RHEA:41251)

UniProt features (19 total): sequence variant 7, binding site 5, domain 2, sequence conflict 2, chain 1, mutagenesis site 1, splice variant 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
6VB2	X-RAY DIFFRACTION	1.41

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BYJ1-F1	91.59	0.78

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 (5): 408; 413; 588; 592; 711

Mutagenesis-validated functional residues (1):

Position	Phenotype
451	increases the o2-dependent dioxygenase activity.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-2142712	Synthesis of 12-eicosatetraenoic acid derivatives
R-HSA-1430728	Metabolism
R-HSA-2142753	Arachidonate metabolism
R-HSA-556833	Metabolism of lipids
R-HSA-8978868	Fatty acid metabolism

MSigDB gene sets: 263 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_UP, GOBP_LIPID_MODIFICATION, GOBP_EPITHELIUM_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_LONG_CHAIN_FATTY_ACID_METABOLIC_PROCESS, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, NAGASHIMA_NRG1_SIGNALING_UP, GOBP_ORGANIC_ACID_BIOSYNTHETIC_PROCESS, FERREIRA_EWINGS_SARCOMA_UNSTABLE_VS_STABLE_DN, GOBP_CERAMIDE_BIOSYNTHETIC_PROCESS, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, GOBP_SENSORY_PERCEPTION_OF_PAIN, GOBP_LIPOXYGENASE_PATHWAY, GOBP_SPHINGOLIPID_METABOLIC_PROCESS

GO Biological Process (13): sphingolipid metabolic process (GO:0006665), sensory perception of pain (GO:0019233), arachidonate metabolic process (GO:0019369), lipoxygenase pathway (GO:0019372), lipid oxidation (GO:0034440), peroxisome proliferator activated receptor signaling pathway (GO:0035357), linoleic acid metabolic process (GO:0043651), fat cell differentiation (GO:0045444), ceramide biosynthetic process (GO:0046513), hepoxilin biosynthetic process (GO:0051122), establishment of skin barrier (GO:0061436), lipid metabolic process (GO:0006629), fatty acid metabolic process (GO:0006631)

GO Molecular Function (11): iron ion binding (GO:0005506), oxidoreductase activity, acting on single donors with incorporation of molecular oxygen, incorporation of two atoms of oxygen (GO:0016702), intramolecular hydroxytransferase activity (GO:0050486), hydroperoxy icosatetraenoate isomerase activity (GO:0106255), hydroperoxy icosatetraenoate dehydratase activity (GO:0106256), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), lyase activity (GO:0016829), isomerase activity (GO:0016853), metal ion binding (GO:0046872), dioxygenase activity (GO:0051213)

GO Cellular Component (3): cytosol (GO:0005829), membrane (GO:0016020), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Arachidonate metabolism	1
Fatty acid metabolism	1
Metabolism	1
Metabolism of lipids	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
catalytic activity	3
cellular anatomical structure	3
lipid metabolic process	2
long-chain fatty acid metabolic process	2
icosanoid metabolic process	2
unsaturated fatty acid metabolic process	2
olefinic compound metabolic process	2
sensory perception	1
fatty acid metabolic process	1
lipid modification	1
nuclear receptor-mediated signaling pathway	1
cell differentiation	1
ceramide metabolic process	1
sphingolipid biosynthetic process	1
long-chain fatty acid biosynthetic process	1
skin epidermis development	1
primary metabolic process	1
monocarboxylic acid metabolic process	1
transition metal ion binding	1
oxidoreductase activity, acting on single donors with incorporation of molecular oxygen	1
dioxygenase activity	1
intramolecular transferase activity	1
intramolecular hydroxytransferase activity	1
hydro-lyase activity	1
binding	1
cation binding	1
oxidoreductase activity	1
cytoplasm	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1006 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ALOXE3	NIPAL4	Q0D2K0	923
ALOXE3	TGM1	P22735	872
ALOXE3	ABHD5	Q8WTS1	866
ALOXE3	CYP4F22	Q6NT55	860
ALOXE3	LOX	P28300	803
ALOXE3	PNPLA1	Q8N8W4	797
ALOXE3	ABCA12	Q86UK0	794
ALOXE3	CERS3	Q8IU89	715
ALOXE3	LIPN	Q5VXI9	680
ALOXE3	SDR9C7	Q8NEX9	663
ALOXE3	TINCR	A0A2R8Y7D0	591
ALOXE3	SULT2B1	O00204	571
ALOXE3	CASP14	P31944	554
ALOXE3	SLC27A4	Q6P1M0	520
ALOXE3	SPINK5	Q9NQ38	458

IntAct

53 interactions, top by confidence:

A	B	Type	Score
PRKAG2	PRKAB2	psi-mi:“MI:0914”(association)	0.730
GLIPR1	ALOXE3	psi-mi:“MI:0915”(physical association)	0.560
MORN3	ALOXE3	psi-mi:“MI:0914”(association)	0.560
YY1	ALOXE3	psi-mi:“MI:0915”(physical association)	0.560
ZNF76	ALOXE3	psi-mi:“MI:0915”(physical association)	0.560
GLIPR1	ALOXE3	psi-mi:“MI:0914”(association)	0.560
MORN3	ALOXE3	psi-mi:“MI:0915”(physical association)	0.560
ZSCAN12	A2ML1	psi-mi:“MI:0914”(association)	0.530
CCDC27	ALOX12B	psi-mi:“MI:0914”(association)	0.530
DPPA4	ALOX12B	psi-mi:“MI:0914”(association)	0.530
B3GALNT1	DUSP14	psi-mi:“MI:0914”(association)	0.530
TBC1D22B	A2ML1	psi-mi:“MI:0914”(association)	0.530
NDUFS5	NDUFS4	psi-mi:“MI:0914”(association)	0.530
ZIC1	CTSV	psi-mi:“MI:0914”(association)	0.530
RNF6	ALOX5	psi-mi:“MI:0914”(association)	0.530
ALOXE3	HSPA8	psi-mi:“MI:0914”(association)	0.530
ALOXE3	ALOX12B	psi-mi:“MI:2364”(proximity)	0.470
ALOX12B	ALOXE3	psi-mi:“MI:0915”(physical association)	0.470
ALPK1	ALOXE3	psi-mi:“MI:0915”(physical association)	0.400
ZIC1	IMPA2	psi-mi:“MI:0914”(association)	0.350
ALOXE3	HSPD1	psi-mi:“MI:0914”(association)	0.350
NECTIN2	SERPINA12	psi-mi:“MI:0914”(association)	0.350
BEX5	A2ML1	psi-mi:“MI:0914”(association)	0.350
TLR7	A2ML1	psi-mi:“MI:0914”(association)	0.350
ZNF154	A2ML1	psi-mi:“MI:0914”(association)	0.350

BioGRID (70): ALOXE3 (Affinity Capture-MS), ALOXE3 (Affinity Capture-MS), ALOXE3 (Affinity Capture-MS), ALOXE3 (Affinity Capture-MS), ALOXE3 (Affinity Capture-MS), ALOXE3 (Affinity Capture-MS), ALOXE3 (Affinity Capture-MS), ALOXE3 (Affinity Capture-MS), NBEA (Affinity Capture-MS), ZFHX4 (Affinity Capture-MS), DNAAF2 (Affinity Capture-MS), SRC (Affinity Capture-MS), HSPA8 (Affinity Capture-MS), ALOXE3 (Affinity Capture-MS), ALOXE3 (Affinity Capture-MS)

ESM2 similar proteins: A6H603, D3ZBP4, D3ZKX9, D3ZQF9, F1LQ70, O00329, O00411, O15296, O35936, O43548, O70582, O75342, O95932, P09917, P0C869, P0C871, P12527, P12530, P16050, P16452, P16469, P18054, P27479, P39654, P39655, P48999, P49222, P51399, P52630, P55249, Q02759, Q149M9, Q2KMM4, Q2TB18, Q4R7D0, Q50L43, Q5R5N9, Q5RBE8, Q5RCY5, Q68DD2

Diamond homologs: C8YR32, D3ZKX9, D3ZQF9, F1LQ70, O15296, O16025, O22507, O22508, O24371, O24379, O35936, O70582, O75342, P08170, P09186, P09439, P09917, P09918, P12527, P12530, P16050, P16469, P18054, P24095, P27479, P27480, P27481, P37831, P38414, P38417, P38418, P39654, P39655, P48999, P51399, P55249, Q02759, Q2KMM4, Q41238, Q43190

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	48
Likely pathogenic	21
Uncertain significance	157
Likely benign	51
Benign	50

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1176368	GRCh37/hg19 17p13.1(chr17:7999945-8015514)x1	Pathogenic
1323064	NM_021628.3(ALOXE3):c.1432del (p.Ser478fs)	Pathogenic
1377327	NM_021628.3(ALOXE3):c.1964del (p.Leu655fs)	Pathogenic
1879361	NM_021628.3(ALOXE3):c.1573G>T (p.Glu525Ter)	Pathogenic
2116533	NM_021628.3(ALOXE3):c.1583del (p.Gly528fs)	Pathogenic
217300	NC_000017.11:g.8017296_8022594del	Pathogenic
217301	NM_021628.3(ALOXE3):c.418C>T (p.Arg140Ter)	Pathogenic
2707692	NM_021628.3(ALOXE3):c.1181G>A (p.Trp394Ter)	Pathogenic
279677	NM_021628.3(ALOXE3):c.1889C>T (p.Pro630Leu)	Pathogenic
3407	NM_021628.3(ALOXE3):c.1498G>T (p.Val500Phe)	Pathogenic
3408	NM_021628.3(ALOXE3):c.700C>T (p.Arg234Ter)	Pathogenic
3409	NM_021628.3(ALOXE3):c.1186C>A (p.Arg396Ser)	Pathogenic
3620009	NM_021628.3(ALOXE3):c.784+1G>A	Pathogenic
3680649	NM_021628.3(ALOXE3):c.367C>T (p.Gln123Ter)	Pathogenic
39548	NM_021628.3(ALOXE3):c.842G>T (p.Gly281Val)	Pathogenic
39551	NM_021628.3(ALOXE3):c.1280T>C (p.Leu427Pro)	Pathogenic
449286	NM_021628.3(ALOXE3):c.1630C>T (p.Gln544Ter)	Pathogenic
4847442	NM_021628.3(ALOXE3):c.1078dup (p.Ala360fs)	Pathogenic
617845	NC_000017.11:g.8113975_8119273delinsC	Pathogenic
620330	NM_021628.3(ALOXE3):c.1329C>A (p.Tyr443Ter)	Pathogenic
633810	NM_021628.3(ALOXE3):c.306T>A (p.Tyr102Ter)	Pathogenic
633811	NM_021628.3(ALOXE3):c.834C>A (p.Tyr278Ter)	Pathogenic
72354	NM_021628.3(ALOXE3):c.631C>T (p.Arg211Ter)	Pathogenic
817655	NM_021628.3(ALOXE3):c.1096del (p.Ile366fs)	Pathogenic
973092	NM_021628.3(ALOXE3):c.1954C>T (p.Gln652Ter)	Pathogenic
982895	NM_021628.3(ALOXE3):c.680+1G>A	Pathogenic
995448	NM_021628.3(ALOXE3):c.1193C>T (p.Ser398Phe)	Pathogenic
995449	NM_021628.3(ALOXE3):c.758del (p.Phe253fs)	Pathogenic
995450	NM_021628.3(ALOXE3):c.957G>A (p.Glu319=)	Pathogenic
995451	NM_021628.3(ALOXE3):c.327C>A (p.Cys109Ter)	Pathogenic

SpliceAI

2667 predictions. Top by Δscore:

Variant	Effect	Δscore
17:8109173:CCT:C	donor_gain	1.0000
17:8109260:C:CT	acceptor_gain	1.0000
17:8110296:C:CC	acceptor_gain	1.0000
17:8110303:C:CT	acceptor_gain	1.0000
17:8110303:C:T	acceptor_gain	1.0000
17:8110524:CCCCT:C	acceptor_gain	1.0000
17:8110525:CCCT:C	acceptor_gain	1.0000
17:8110525:CCCTC:C	acceptor_gain	1.0000
17:8110526:CCT:C	acceptor_gain	1.0000
17:8110526:CCTC:C	acceptor_gain	1.0000
17:8110527:CT:C	acceptor_gain	1.0000
17:8110527:CTC:C	acceptor_gain	1.0000
17:8110528:TCTGC:T	acceptor_gain	1.0000
17:8110529:C:A	acceptor_gain	1.0000
17:8110529:C:CC	acceptor_gain	1.0000
17:8110530:T:A	acceptor_loss	1.0000
17:8111353:AC:A	donor_gain	1.0000
17:8111354:CC:C	donor_gain	1.0000
17:8111354:CCCA:C	donor_gain	1.0000
17:8111355:CCAC:C	donor_loss	1.0000
17:8111357:ACCT:A	donor_loss	1.0000
17:8111528:TACT:T	acceptor_gain	1.0000
17:8111530:CT:C	acceptor_gain	1.0000
17:8111532:C:CC	acceptor_gain	1.0000
17:8112087:GCTCA:G	donor_loss	1.0000
17:8112088:CTCA:C	donor_loss	1.0000
17:8112089:TCA:T	donor_loss	1.0000
17:8112090:CAC:C	donor_loss	1.0000
17:8112091:A:AC	donor_gain	1.0000
17:8112091:ACTTG:A	donor_loss	1.0000

AlphaMissense

4650 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:8109964:G:C	N448K	0.996
17:8109964:G:T	N448K	0.996
17:8110123:C:G	R425P	0.995
17:8110158:A:C	H413Q	0.995
17:8110158:A:T	H413Q	0.995
17:8110221:C:A	K392N	0.995
17:8110221:C:G	K392N	0.995
17:8110147:T:A	E417V	0.994
17:8110160:G:C	H413D	0.994
17:8096639:G:C	S708R	0.993
17:8096639:G:T	S708R	0.993
17:8096641:T:G	S708R	0.993
17:8116884:A:G	W82R	0.993
17:8116884:A:T	W82R	0.993
17:8108516:A:G	W546R	0.992
17:8108516:A:T	W546R	0.992
17:8109952:C:A	R452S	0.992
17:8109952:C:G	R452S	0.992
17:8110210:C:G	R396P	0.992
17:8110092:C:A	K435N	0.991
17:8110092:C:G	K435N	0.991
17:8110124:G:T	R425S	0.990
17:8110173:G:C	H408Q	0.990
17:8110173:G:T	H408Q	0.990
17:8110217:A:G	W394R	0.990
17:8110217:A:T	W394R	0.990
17:8114516:C:A	K216N	0.990
17:8114516:C:G	K216N	0.990
17:8109956:G:T	A451E	0.989
17:8110197:G:C	F400L	0.989

dbSNP variants (sampled 300 via entrez): RS1000057491 (17:8120313 C>G,T), RS1000149812 (17:8107480 A>G), RS1000175282 (17:8113716 CA>C), RS1000236166 (17:8106667 A>C), RS1000265654 (17:8106426 T>G), RS1000429982 (17:8120372 C>G,T), RS1000501849 (17:8120838 C>A,T), RS1000546691 (17:8099051 G>T), RS1000561955 (17:8105609 G>A,C), RS1000593112 (17:8105338 G>A), RS1000738871 (17:8118882 C>G,T), RS1000899080 (17:8103930 T>C), RS1000955603 (17:8116094 A>G), RS1001157668 (17:8110618 G>A,C), RS1001266825 (17:8107518 C>A)

Disease associations

OMIM: gene MIM:607206 | disease phenotypes: MIM:606545, MIM:242100, MIM:242300, MIM:614602

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal recessive congenital ichthyosis 3	Definitive	Autosomal recessive
congenital non-bullous ichthyosiform erythroderma	Strong	Autosomal recessive
self-healing collodion baby	Supportive	Autosomal recessive
lamellar ichthyosis	Supportive	Autosomal recessive

Mondo (9): autosomal recessive congenital ichthyosis 3 (MONDO:0011680), lamellar ichthyosis (MONDO:0017778), ichthyosis (MONDO:0019269), breast ductal adenocarcinoma (MONDO:0005590), autosomal recessive congenital ichthyosis 2 (MONDO:0009439), autosomal recessive congenital ichthyosis (MONDO:0017265), congenital non-bullous ichthyosiform erythroderma (MONDO:0019306), trichohepatoenteric syndrome 2 (MONDO:0013818), self-healing collodion baby (MONDO:0017267)

Orphanet (6): Lamellar ichthyosis (Orphanet:313), Ichthyosis (Orphanet:79354), Self-improving collodion baby (Orphanet:281122), Congenital ichthyosiform erythroderma (Orphanet:79394), Autosomal recessive congenital ichthyosis (Orphanet:281097), Trichohepatoenteric syndrome (Orphanet:84064)

HPO phenotypes

49 total (30 of 49 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000083	Renal insufficiency
HP:0000164	Abnormality of the dentition
HP:0000232	Everted lower lip vermilion
HP:0000365	Hearing impairment
HP:0000389	Chronic otitis media
HP:0000491	Keratitis
HP:0000656	Ectropion
HP:0000958	Dry skin
HP:0000962	Hyperkeratosis
HP:0000966	Hypohidrosis
HP:0000970	Anhidrosis
HP:0000982	Palmoplantar keratoderma
HP:0000989	Pruritus
HP:0001019	Erythroderma
HP:0001376	Limitation of joint mobility
HP:0001508	Failure to thrive
HP:0001510	Growth delay
HP:0001595	Abnormal hair morphology
HP:0001596	Alopecia
HP:0001597	Abnormal nail morphology
HP:0001792	Small nail
HP:0001816	Thin nail
HP:0001831	Short toe
HP:0001944	Dehydration
HP:0002046	Heat intolerance
HP:0002205	Recurrent respiratory infections
HP:0003241	External genital hypoplasia
HP:0003470	Paralysis
HP:0003577	Congenital onset

GWAS associations

0 associations (top):

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D018270	Carcinoma, Ductal, Breast	C04.557.470.200.025.232.500; C04.557.470.615.132.500; C04.588.180.390; C17.800.090.500.390
D007057	Ichthyosis	C16.131.831.512; C16.614.492; C17.800.428.333; C17.800.804.512
C564699	Ichthyosis, Lamellar, 5 (supp.)
C565473	Self-Healing Collodion Baby (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — Lipoxygenases

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases methylation, increases expression	2
Aflatoxin B1	decreases methylation, increases methylation	2
Cadmium Chloride	increases expression	2
aristolochic acid I	increases expression	1
sotorasib	affects cotreatment, decreases expression	1
sodium arsenate	decreases expression, increases abundance	1
2-methyl-4-isothiazolin-3-one	increases expression	1
terbufos	affects response to substance	1
beta-lapachone	increases expression	1
sodium arsenite	increases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
hydroquinone	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment	1
cyclohexyl methylphosphonofluoridate	increases expression	1
perfluorooctane sulfonic acid	increases expression	1
abrine	increases expression	1
licochalcone B	increases expression	1
bisphenol S	increases methylation	1
jinfukang	affects cotreatment, decreases expression	1
trametinib	affects cotreatment, decreases expression	1
(+)-JQ1 compound	decreases expression	1
NVP-BKM120	affects cotreatment, decreases expression	1
Acetaminophen	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Arsenic	decreases expression, increases abundance	1
Camptothecin	increases expression	1
Cannabidiol	increases expression	1
Cisplatin	affects cotreatment, decreases expression	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04996485	PHASE4	UNKNOWN	Scientific Substantiation and Assessment of the Effectiveness of Pathogenetic Methods of Therapy for Congenital Ichthyosis in Children
NCT01222000	PHASE3	UNKNOWN	Treatment of the Recessive Nonbullous Congenital Ichthyosis by the Epigallocatechine Cutaneous
NCT00004690	PHASE3	COMPLETED	Phase III Study of Monolaurin Cream Therapy for Patients With Congenital Ichthyosis
NCT05295732	PHASE3	COMPLETED	The ASCEND Study: Evaluating TMB-001 in the Treatment of RXLI or ARCI Ichthyosis
NCT03414970	PHASE3	ACTIVE_NOT_RECRUITING	Hypofractionated Radiation Therapy After Mastectomy in Preventing Recurrence in Patients With Stage IIa-IIIa Breast Cancer
NCT03041038	PHASE2	COMPLETED	The Efficacy and Safety of Secukinumab in Patients With Ichthyoses
NCT03738800	PHASE2	TERMINATED	A Safety, Efficacy and Systemic Exposure Study of CD5789 Cream in Adults and Adolescents With Lamellar Ichthyosis
NCT02864082	PHASE2	COMPLETED	A Safety and Tolerability Study of Topical PAT-001 in Congenital Ichthyosis
NCT04154293	PHASE2	COMPLETED	A Vehicle Controlled Study to Evaluate Safety and Efficacy of Topical TMB-001 for Treatment of Congenital Ichthyosis
NCT04697056	PHASE2	TERMINATED	A Study to Evaluate the Efficacy and Safety of Imsidolimab (ANB019) in the Treatment of Participants With Ichthyosis
NCT06136403	PHASE2	RECRUITING	A 44-week Monocentric Open Study Assessing the Efficacy and Safety of Deucravacitinib in Adults With Inflammatory Genodermatoses
NCT06362447	PHASE2	NOT_YET_RECRUITING	Efficacy of Injectable Gentamicin in Hereditary Ichthyosis
NCT00461344	PHASE2	TERMINATED	Docetaxel + Doxorubicin as Neoadjuvant Chemotherapy in Patients With Breast Cancer
NCT07499999	PHASE2	NOT_YET_RECRUITING	Randomized Double-Blind Phase II Trial of Baby Exemestane Versus Baby Tamoxifen in Post-Menopausal Women at High Risk for Breast Cancer
NCT00001292	Not specified	COMPLETED	Study of Scaling Disorders and Other Inherited Skin Diseases
NCT04549792	EARLY_PHASE1	COMPLETED	An Open-Label and Long-Term Extension Study to Evaluate the Efficacy and Safety of Ustekinumab in the Treatment of Patients With Ichthyoses
NCT07050810	EARLY_PHASE1	ENROLLING_BY_INVITATION	Thera-Clean® Microbubbles System in Patients With Skin Diseases
NCT00074685	Not specified	COMPLETED	National Registry for Ichthyosis and Related Disorders
NCT02655861	Not specified	TERMINATED	A Multi-center, Prospective Evaluation of Infants and Children With Congenital Ichthyosis
NCT03051347	Not specified	COMPLETED	Asthma and Atopic Dermatitis Validation of PROMIS Pediatric Instruments
NCT03417856	Not specified	ENROLLING_BY_INVITATION	Defining the Skin and Blood Biomarkers of Ichthyosis
NCT03464994	Not specified	COMPLETED	Ophthalmological Abnormalities in Hereditary Ichthyosis (ICHTYO-KERATO)
NCT03641261	Not specified	COMPLETED	Therapeutic Education Using an Internet Application in Hereditary Ichthyosis
NCT03796052	Not specified	COMPLETED	Study Determining Safety and Efficacy of Avena Sativa (Oat) Skincare Products for Treating Skin Dryness and Itching in Cancer Patients
NCT05610306	Not specified	COMPLETED	Quality of Life in Middle-aged and Older Patients With Congenital Ichthyosis
NCT05954416	Not specified	RECRUITING	FARD (RaDiCo Cohort) (RaDiCo-FARD)
NCT06123091	Not specified	UNKNOWN	Exploring Patient Reported Outcomes in Inherited Ichthyosis
NCT06330324	Not specified	ENROLLING_BY_INVITATION	Reproductive Options in Inherited Skin Diseases
NCT06330350	Not specified	RECRUITING	Qualitative Study in Patients With Genodermatoses and Healthcare Professionals on Reproductive Counselling
NCT07066150	Not specified	COMPLETED	A Clinical Evaluation of Marula-Derived Ceramide Cream on Skin Barrier Function Enhancement
NCT00637364	PHASE1/PHASE2	SUSPENDED	High Intensity Focused Ultrasound Tumor Treatment for Pancreatic Cancer Pain
NCT02779855	PHASE1/PHASE2	COMPLETED	Talimogene Laherparepvec in Combination With Neoadjuvant Chemotherapy in Triple Negative Breast Cancer
NCT01753908	EARLY_PHASE1	COMPLETED	Broccoli Sprout Extract in Treating Patients With Breast Cancer
NCT01796041	EARLY_PHASE1	COMPLETED	Intraoperative Imaging of Breast Cancer With Indocyanine Green
NCT01208974	Not specified	ACTIVE_NOT_RECRUITING	Nipple-Areola Complex (NAC) Irradiation After Nipple-Sparing Mastectomy and Reconstruction
NCT01875198	Not specified	TERMINATED	Oncologic Impact of Splenectomy-omitting Radical Pancreatectomy in Well-selected Left-sided Pancreatic Cancer
NCT03543397	Not specified	UNKNOWN	MRI in Ductal Carcinoma in Situ (DCIS)
NCT03834532	Not specified	COMPLETED	Living Well After Breast Surgery
NCT05312073	Not specified	COMPLETED	Study of in Vivo and in Vitro Transcriptomic and Proteomic Signatures in Unhereditary Ichtyosis