ALOXE3

protein-coding

arachidonate lipoxygenase 3, the group of Arachidonate lipoxygenases

Gene summary

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.[provided by RefSeq, Sep 2009]

MANE transcript

NM_021628.3

Inheritance

ClinVar variants

P:81U:143B:53

Top phenotype

Ichthyosis, congenital, autosomal recessive 3

gnomAD constraint

pLI —, LoF o/e 0.8

Max pathogenic AF

—

Genomic locus

chr17:8,095,900-8,119,047

External References & Databases

Ensembl (ENSG00000179148)

Transcript & Mutation Effects

hg38 • Region Span ~23.1 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

congenital non-bullous ichthyosiform erythrodermaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019306

Submitter: Orphanet

lamellar ichthyosisSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0017778

Submitter: Orphanet

self-healing collodion babySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0017267

Submitter: Orphanet

autosomal recessive congenital ichthyosis 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011680

Submitter: PanelApp Australia

autosomal recessive congenital ichthyosis 3DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011680

Submitter: G2P

autosomal recessive congenital ichthyosis 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011680

Submitter: Genomics England PanelApp

autosomal recessive congenital ichthyosis 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011680

Submitter: Labcorp Genetics (formerly Invitae)

congenital non-bullous ichthyosiform erythrodermaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0019306

Submitter: Genomics England PanelApp

Clinical Genomic Database (CGD)

Ichthyosis, congenital, autosomal recessive 3AR

Manifestation: Dermatologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 11773004; 16116617; 19131948; 20301593

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ALOXE3 variants in ClinVar

42 Conditions Cataloged

not providedTotal: 131

Inborn genetic diseasesTotal: 118

Autosomal recessive congenital ichthyosis 3Total: 101

ALOXE3-related disorderTotal: 22

not specifiedTotal: 17

Lamellar ichthyosisTotal: 9

Autosomal recessive congenital ichthyosis 2Total: 7

Ichthyosis and erythrokeratodermaTotal: 6

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_021628.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous	1 clinvar		5 clinvar	29 clinvar	3 clinvar	38
missense	9 clinvar	14 clinvar	135 clinvar	18 clinvar	3 clinvar	179
nonsense	14 clinvar	7 clinvar	2 clinvar			23
start loss	1 clinvar		1 clinvar			2
frameshift	12 clinvar	6 clinvar				18
splice donor/acceptor (+/-2bp)	8 clinvar	9 clinvar				17
Total	45	36	143	47	6	277

Highest pathogenic variant AF is 0.0017414975

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 18 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_021628.3	RefSeq	NP_067641.2	15	MANE Select
ENST00000448843.7	Ensembl	ENSP00000400581.2	15	MANE Select
NM_001165960.1	RefSeq	NP_001159432.1	16	Standard
NM_001369446.1	RefSeq	NP_001356375.1	15	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Metabolism of lipids
Synthesis of 12-eicosatetraenoic acid derivatives
Arachidonic acid metabolism
Metabolism
Fatty acid metabolism

Biological Process

sphingolipid metabolic process
sensory perception of pain
arachidonic acid metabolic process
lipoxygenase pathway
peroxisome proliferator activated receptor signaling pathway

Molecular Function

iron ion binding
protein binding
oxidoreductase activity, acting on single donors with incorporation of molecular oxygen, incorporation of two atoms of oxygen
lyase activity
hepoxilin A3 synthase activity

Cellular Component

cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000318227
Coding exons: 16
Length: 23148
Individuals with no LoFs: 125636
Homozygous LoFs: 0
Heterozygous LoFs: 112
Defined: 125748
p: 0.000445

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.149	471	480	0.981	0.0000276	5441
Missense (PolyPhen)		145	160.07	0.90586		1963
Synonymous	0.414	196	204	0.963	0.0000116	1717
Loss of Function	1.26	35	44.0	0.795	0.00000235	458

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.00026	0.00020	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.00087	0.00087	rare
Finnish	0.00042	0.00042	rare
European (Non-Finnish)	0.00052	0.00052	rare
South Asian	0.00043	0.00042	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Non-heme iron-containing lipoxygenase which is atypical in that it displays a prominent hydroperoxide isomerase activity and a reduced dioxygenase activity compared to other lipoxygenases. The hydroperoxide isomerase activity catalyzes the isomerization of hydroperoxides, derived from arachidonic and linoleic acid by ALOX12B, into hepoxilin-type epoxyalcohols. The dioxygenase activity requires a step of activation of the enzyme by molecular oxygen. 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. Plays also 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. {ECO:0000269|PubMed:12881489, ECO:0000269|PubMed:17045234, ECO:0000269|PubMed:20921226, ECO:0000269|PubMed:20923767, ECO:0000269|PubMed:21558561}.;

Recessive Scores

pRec: 0.154

Intolerance Scores

LoFtool: 0.146
RVIS EVS: -1
RVIS percentile EVS: 8.54

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.447

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium