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ALOXE3
arachidonate epidermal lipoxygenase 3
The ALOXE3 gene provides instructions for making an enzyme called eLOX3, which is essential for maintaining the skin's protective barrier and preventing dehydration. ALOXE3 encodes the eLOX3 enzyme, part of a family of arachidonate lipoxygenases.
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, provides the genetic blueprint for an enzyme called eLOX3. This enzyme is crucial for the proper development and function of the skin's outermost layer, the epidermis. Specifically, eLOX3 contributes to the formation of lipid layers that are vital for preventing excessive water loss from the body.
Pathogenic variants in the ALOXE3 gene can impair the skin's barrier function, leading to a range of inherited skin conditions, primarily those characterised by dry, scaly skin.
What the gene does
The ALOXE3 gene directs the synthesis of the eLOX3 enzyme, which belongs to the arachidonate lipoxygenase enzyme family. While many enzymes in this family directly add oxygen molecules to fatty acids to create fatty acid hydroperoxides, eLOX3 operates at a subsequent step in this biochemical pathway. Instead of initiating the oxygenation, eLOX3 processes these pre-existing fatty acid hydroperoxides.
These processed hydroperoxides are then converted into signalling molecules. These molecules are instrumental in the complex process of forming the lipid layers within the stratum corneum, the outermost part of the epidermis. These organised lipid layers are fundamental for the skin's barrier function, effectively preventing dehydration by limiting transepidermal water loss.
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Chromosome location
The ALOXE3 gene is situated on chromosome 17. Its specific location is at position 17p13.1, which refers to the short (p) arm of chromosome 17 at region 13.1. This genomic address specifies where ALOXE3 resides within the human genome.
Protein structure
The eLOX3 protein, encoded by the ALOXE3 gene, consists of 711 amino acids. It features two main functional regions or domains. The N-terminal region, spanning amino acids 2 to 119, is known as the PLAT domain. Following this, the larger C-terminal portion, from amino acids 120 to 711, constitutes the Lipoxygenase domain, which is central to the enzyme's catalytic activity.
Key variants
Variants within the ALOXE3 gene can alter the structure or function of the eLOX3 enzyme. These genetic changes can range from single nucleotide substitutions to larger deletions or insertions. When such variants lead to a non-functional or improperly functioning enzyme, they can disrupt the critical processes involved in maintaining the skin barrier.
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 | ★★☆☆ | Autosomal recessive congenital ichthyosis 3 |
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 disorders, particularly those classified as ichthyoses. These conditions primarily affect the skin, leading to symptoms such as redness, scaling, and an impaired skin barrier. A compromised skin barrier can increase susceptibility to infections and lead to excessive water loss from the skin.
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 recognised within the NHS Genomic Medicine Service. It is listed on several Green RAG (Red Amber Green) rated panels in PanelApp UK, indicating strong evidence for its involvement in associated conditions. These include panels for Autosomal recessive congenital ichthyosis, Foetal anomalies (R21), Ichthyosis and erythrokeratoderma (R165), Palmoplantar keratoderma and erythrokeratodermas, and Palmoplantar keratodermas (R166).
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main role of the ALOXE3 gene?
The ALOXE3 gene provides instructions for making the eLOX3 enzyme. This enzyme is crucial for processing certain fatty acid hydroperoxides, which are then converted into signalling molecules essential for building the lipid layers of the skin's outermost barrier.
How do variants in ALOXE3 affect health?
Variants in the ALOXE3 gene can disrupt the normal function of the eLOX3 enzyme. This impairment can lead to a defective skin barrier, resulting in inherited skin conditions characterised by dryness, scaling, redness, and increased susceptibility to dehydration and infections.
What type of conditions are associated with ALOXE3?
ALOXE3 gene variants are primarily associated with forms of ichthyosis, which are a group of inherited skin disorders. These conditions typically manifest with symptoms affecting the skin's appearance and protective function, such as excessive scaling and redness.
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