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ALOXE3
arachidonate epidermal lipoxygenase 3
The ALOXE3 gene provides instructions for the eLOX3 enzyme, which plays a crucial role in forming the skin's protective lipid barrier. The ALOXE3 gene encodes the eLOX3 enzyme, part of the arachidonate lipoxygenase family.
ALOXE3 is located on the short (p) arm of chromosome 17, at band 17p13.1. Arm ratio per GRCh38 - banding schematic.
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Overview
The ALOXE3 gene, also known as arachidonate epidermal lipoxygenase 3, is responsible for producing the eLOX3 enzyme. This enzyme is integral to the proper formation and function of the skin's outermost layer, the epidermis. Specifically, it helps create the essential lipid barriers that prevent dehydration and protect the body from environmental factors.
Pathogenic variants in the ALOXE3 gene are inherited in an autosomal recessive manner and are associated with certain inherited skin conditions, primarily various forms of ichthyosis.
What the gene does
The ALOXE3 gene provides the blueprint for the eLOX3 enzyme, a member of the arachidonate lipoxygenase enzyme family. Unlike other members of this family that directly add oxygen molecules to fatty acids to create fatty acid hydroperoxides, eLOX3 is involved in the subsequent processing steps. It acts on these fatty acid hydroperoxides, converting them into signalling molecules.
These signalling molecules are crucial for assembling the lipid layers within the epidermis. The integrity of these lipid layers is paramount for the skin's barrier function, preventing excessive water loss and protecting against external aggressors. Disruptions in eLOX3 function due to genetic variants can compromise this barrier, leading to various skin abnormalities.
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Chromosome location
The ALOXE3 gene is located on chromosome 17 at position 13.1 (17p13.1). The protein it encodes is 711 amino acids in length.
Protein structure
The eLOX3 enzyme, encoded by the ALOXE3 gene, consists of two main domains. The PLAT domain spans amino acids 2 to 119, while the larger Lipoxygenase domain is located from amino acids 120 to 711. This Lipoxygenase domain is responsible for the enzyme's catalytic activity in processing fatty acid hydroperoxides.
Key variants
Variants in the ALOXE3 gene can alter the function of the eLOX3 enzyme, leading to impaired lipid barrier formation in the skin. These genetic changes are typically inherited in an autosomal recessive pattern, meaning an individual must inherit two copies of a pathogenic variant (one from each parent) to be affected.
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.1630C>T | p.Gln544Ter | Pathogenic | ★★☆☆ | Ichthyosis and erythrokeratoderma |
c.1889C>T | p.Pro630Leu | Pathogenic/Likely pathogenic | ★★☆☆ | Ichthyosis and erythrokeratoderma |
c.2065C>T | p.Arg689Trp | Pathogenic/Likely pathogenic | ★★☆☆ | Lamellar ichthyosis |
c.434G>A | p.Arg145His | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.631C>T | p.Arg211Ter | Pathogenic | ★★☆☆ | ALOXE3-related disorder |
c.680+1G>A | - | Pathogenic | ★★☆☆ | Autosomal recessive congenital ichthyosis 3 |
c.700C>T | p.Arg234Ter | Pathogenic | ★★☆☆ | ALOXE3-related disorder |
c.834C>A | p.Tyr278Ter | Pathogenic | ★★☆☆ | Autosomal recessive congenital ichthyosis 3 |
c.1654del | p.Ala552fs | Pathogenic | ★☆☆☆ | Ichthyosis and erythrokeratoderma |
c.367C>T | p.Gln123Ter | Pathogenic | ★☆☆☆ | not provided |
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 in the ALOXE3 gene are associated with inherited skin conditions, including nonbullous congenital ichthyosiform erythroderma. This condition is characterised by red, scaly skin and an increased risk of infection and dehydration due to a compromised skin barrier.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic ALOXE3 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 ALOXE3 gene is included in several UK NHS national genomic testing panels. These panels cover conditions such as Autosomal recessive congenital ichthyosis, Foetal anomalies (R21), Ichthyosis and erythrokeratoderma (R165), Palmoplantar keratoderma and erythrokeratodermas, and Palmoplantar keratodermas (R166). This indicates its recognised clinical significance within the NHS Genomic Medicine Service.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the ALOXE3 gene?
The ALOXE3 gene provides instructions for the eLOX3 enzyme, which is crucial for processing fatty acid hydroperoxides. These processed molecules then contribute to forming the essential lipid layers in the skin's outermost barrier, preventing water loss.
What condition is associated with ALOXE3 gene variants?
Pathogenic variants in the ALOXE3 gene are primarily associated with nonbullous congenital ichthyosiform erythroderma, an inherited skin disorder characterised by redness, scaling, and increased susceptibility to dehydration and infections.
How are ALOXE3 gene variants inherited?
Variants in the ALOXE3 gene are inherited in an autosomal recessive manner. This means that an individual must inherit two copies of a pathogenic variant, one from each parent, to develop a condition associated with this gene.
References
- Mashima R, Okuyama T. The role of lipoxygenases in pathophysiology; new insights and future perspectives. Redox biology. 2015. PMID: 26298204
- Krieg P, Fürstenberger G. The role of lipoxygenases in epidermis. Biochimica et biophysica acta. 2014. PMID: 23954555
- Eckl KM, de Juanes S, Kurtenbach J. Molecular analysis of 250 patients with autosomal recessive congenital ichthyosis: evidence for mutation hotspots in ALOXE3 and allelic heterogeneity in ALOX12B. The Journal of investigative dermatology. 2009. PMID: 19131948
- Eckl KM, Krieg P, Küster W. Mutation spectrum and functional analysis of epidermis-type lipoxygenases in patients with autosomal recessive congenital ichthyosis. Human mutation. 2005. PMID: 16116617
- Jobard F, Lefèvre C, Karaduman A. Lipoxygenase-3 (ALOXE3) and 12(R)-lipoxygenase (ALOX12B) are mutated in non-bullous congenital ichthyosiform erythroderma (NCIE) linked to chromosome 17p13.1. Human molecular genetics. 2002. PMID: 11773004