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ALOX12B
arachidonate 12-lipoxygenase, 12R type
The ALOX12B gene provides instructions for the 12R-LOX enzyme, which is vital for developing the skin's protective lipid layers and preventing dehydration. The ALOX12B gene is responsible for producing the 12R-LOX enzyme, an arachidonate lipoxygenase that plays a key role in skin barrier function.
ALOX12B 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 ALOX12B gene encodes an enzyme called arachidonate 12-lipoxygenase, 12R type, often referred to as 12R-LOX. This enzyme is a member of the arachidonate lipoxygenase family, which generally functions by adding an oxygen molecule to specific fatty acids.
In the context of the skin, the 12R-LOX enzyme is particularly important for its role in forming the lipid layers within the epidermis. These lipid layers are fundamental to the skin's barrier function, helping to prevent dehydration and protect against external factors.
What the gene does
The 12R-LOX enzyme, encoded by ALOX12B, facilitates the addition of an oxygen molecule to arachidonic acid, a type of fatty acid. This process results in the production of 12R-hydroperoxyeicosatetraenoic acid (12R-HPETE). Subsequent conversion of 12R-HPETE yields signalling molecules that are integral to the assembly of lipid layers in the outermost layer of the skin, the epidermis.
The formation of these organised lipid layers is critical for establishing an effective skin barrier. This barrier prevents excessive water loss from the body, thereby maintaining proper hydration and protecting the internal environment from external aggressors.
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Chromosome location
The ALOX12B gene is situated on chromosome 17 at position 17p13.1. This genomic location refers to the short (p) arm of chromosome 17, specifically within region 13.1.
Protein structure
The ALOX12B gene encodes a protein consisting of 701 amino acids. This protein contains two main functional regions: the PLAT domain, located at amino acids 2-119, and the Lipoxygenase domain, spanning amino acids 120-701. The Lipoxygenase domain is responsible for the enzymatic activity of adding oxygen to fatty acids.
Key variants
Genetic variations within the ALOX12B gene can alter the function of the 12R-LOX enzyme. These changes can impair the enzyme's ability to facilitate the formation of the skin's lipid barrier, leading to various health implications. Over 55 different pathogenic variants have been identified in the ALOX12B gene.
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.1148C>T | p.Thr383Met | Pathogenic/Likely pathogenic | ★★☆☆ | Autosomal recessive congenital ichthyosis 2 |
c.1158dup | p.Tyr387fs | Pathogenic/Likely pathogenic | ★★☆☆ | Autosomal recessive congenital ichthyosis 2 |
c.1265C>T | p.Pro422Leu | Pathogenic/Likely pathogenic | ★★☆☆ | Autosomal recessive congenital ichthyosis 2 |
c.1272dup | p.Lys425fs | Pathogenic | ★★☆☆ | Lamellar ichthyosis |
c.1463G>A | p.Arg488His | Pathogenic | ★★☆☆ | Lamellar ichthyosis |
c.1625_1626del | p.Lys542fs | Pathogenic | ★★☆☆ | Autosomal recessive congenital ichthyosis 2 |
c.1654+3A>G | - | Pathogenic/Likely pathogenic | ★★☆☆ | Autosomal recessive congenital ichthyosis 2 |
c.1654G>T | p.Gly552Cys | Pathogenic/Likely pathogenic | ★★☆☆ | Lamellar ichthyosis |
c.1926+1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Autosomal recessive congenital ichthyosis 2 |
c.71T>C | p.Leu24Pro | Pathogenic/Likely pathogenic | ★★☆☆ | Lamellar ichthyosis |
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 ALOX12B gene are associated with several inherited skin conditions, primarily forms of ichthyosis. These conditions typically affect the skin's barrier function, leading to symptoms such as redness, scaling, and increased susceptibility to dehydration and infections. Examples include nonbullous congenital ichthyosiform erythroderma (NBCIE) and self-healing collodion baby.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic ALOX12B 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 ALOX12B gene is included in several NHS England Genomic Medicine Service approved panels. These include panels for Autosomal recessive congenital ichthyosis, Foetal anomalies (R21), Ichthyosis and erythrokeratoderma (R165), Palmoplantar keratoderma and erythrokeratodermas, and Palmoplantar keratodermas (R166). This indicates its recognised clinical relevance within the UK for these specific conditions.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the ALOX12B gene?
The ALOX12B gene provides instructions for producing the 12R-LOX enzyme, which is crucial for forming the protective lipid layers in the outermost layer of the skin (epidermis). These layers prevent water loss and maintain skin hydration.
What health conditions are associated with ALOX12B gene variants?
Variants in the ALOX12B gene are primarily associated with inherited skin conditions collectively known as ichthyosis, including nonbullous congenital ichthyosiform erythroderma (NBCIE) and self-healing collodion baby. These conditions affect the skin's barrier function, leading to symptoms like redness, scaling, and dehydration.
How does the ALOX12B gene affect skin barrier function?
The 12R-LOX enzyme, encoded by ALOX12B, helps convert arachidonic acid into signalling molecules that are essential for assembling the lipid layers in the epidermis. These lipid layers are vital for creating a robust skin barrier that protects against water loss and external factors.
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
- Harting M, Brunetti-Pierri N, Chan CS. Self-healing collodion membrane and mild nonbullous congenital ichthyosiform erythroderma due to 2 novel mutations in the ALOX12B gene. Archives of dermatology. 2008. PMID: 18347291
- Yu Z, Schneider C, Boeglin WE. Mutations associated with a congenital form of ichthyosis (NCIE) inactivate the epidermal lipoxygenases 12R-LOX and eLOX3. Biochimica et biophysica acta. 2005. PMID: 15629692
- 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