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ALOX12B
arachidonate 12-lipoxygenase, 12R type
The ALOX12B gene encodes an enzyme crucial for healthy skin barrier formation, and variants in this gene are associated with various forms of ichthyosis. The ALOX12B gene provides instructions for making an enzyme called 12R-LOX.
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, or arachidonate 12-lipoxygenase, 12R type, is responsible for producing the 12R-LOX enzyme. This enzyme is a member of the arachidonate lipoxygenase family, which generally function by adding oxygen molecules to fatty acids, such as arachidonic acid.
Specifically, the 12R-LOX enzyme facilitates the formation of 12R-hydroperoxyeicosatetraenoic acid (12R-HPETE). This compound is then converted into a signalling molecule that is integral to establishing the lipid layers in the epidermis, the skin's outermost layer. These lipid layers are critical for maintaining the skin's barrier function and preventing dehydration.
What the gene does
The ALOX12B gene directs the synthesis of the 12R-LOX enzyme, which is an arachidonate lipoxygenase. Its primary function involves the metabolism of arachidonic acid, a fatty acid, through the addition of an oxygen molecule. This process generates 12R-HPETE. The subsequent conversion of 12R-HPETE into a signalling molecule is crucial for the organisation and structure of the lipid layers within the epidermis. These lipid layers are fundamental to the skin's ability to act as an effective barrier, regulating water retention and preventing excessive moisture loss.
Impairment of this enzymatic function due to genetic variants can compromise the skin barrier, leading to characteristic symptoms observed in associated conditions. The enzyme's role in lipid layer formation highlights its significance for overall skin health and integrity.
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Chromosome location
The ALOX12B gene is situated on chromosome 17, specifically at position 17p13.1. It is inherited in an autosomal recessive pattern, meaning that an individual must inherit two copies of a pathogenic variant (one from each parent) to typically develop an associated condition.
Protein structure
The ALOX12B gene encodes a protein composed of 701 amino acids. This protein features two main functional domains. The N-terminal region, spanning amino acids 2-119, contains the PLAT domain. The larger C-terminal segment, from amino acids 120-701, encompasses the Lipoxygenase domain, which is crucial for its enzymatic activity in fatty acid metabolism.
Key variants
Variants within the ALOX12B gene can alter the function of the 12R-LOX enzyme, which is essential for maintaining skin barrier integrity. Many identified pathogenic variants involve single amino acid changes that disrupt the enzyme's structure or activity. Such variants are typically inherited in an autosomal recessive manner.
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.1192C>T | p.His398Tyr | Pathogenic/Likely pathogenic | ★★☆☆ | ALOX12B-related disorder |
c.1265C>T | p.Pro422Leu | Pathogenic/Likely pathogenic | ★★☆☆ | ALOX12B-related disorder |
c.1272dup | p.Lys425fs | Pathogenic | ★★☆☆ | Autosomal recessive congenital ichthyosis 2 |
c.1463G>A | p.Arg488His | Pathogenic | ★★☆☆ | ALOX12B-related disorder |
c.1625_1626del | p.Lys542fs | Pathogenic | ★★☆☆ | Autosomal recessive congenital ichthyosis 2 |
c.1654+3A>G | - | Pathogenic/Likely pathogenic | ★★☆☆ | Ichthyosis and erythrokeratoderma |
c.1654G>T | p.Gly552Cys | Pathogenic/Likely pathogenic | ★★☆☆ | Lamellar ichthyosis |
c.1926+1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Autosomal recessive congenital ichthyosis 2 |
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 inherited skin conditions, primarily forms of ichthyosis. These include nonbullous congenital ichthyosiform erythroderma (NBCIE), characterised by skin redness, fine scaling, and an increased risk of infection and dehydration. Variants can also lead to conditions such as self-healing collodion baby, where infants are born encased in a tight membrane that sheds within weeks, sometimes preceding NBCIE.
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
ALOX12B is included in several UK NHS national genomic testing panels, reflecting its clinical significance. It is part of the 'Autosomal recessive congenital ichthyosis' panel, the 'Foetal anomalies' panel (R21), the 'Ichthyosis and erythrokeratoderma' panel (R165), the 'Palmoplantar keratoderma and erythrokeratodermas' panel, and the 'Palmoplantar keratodermas' panel (R166).
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the ALOX12B gene?
The ALOX12B gene provides instructions for the 12R-LOX enzyme, which helps form essential lipid layers in the skin's outermost layer (epidermis). These lipid layers are critical for the skin barrier and prevent water loss.
What conditions are associated with ALOX12B gene variants?
Variants in the ALOX12B gene are associated with various inherited skin conditions, including nonbullous congenital ichthyosiform erythroderma (NBCIE) and self-healing collodion baby. These conditions typically affect skin appearance and barrier function.
How is a condition caused by an ALOX12B variant inherited?
Conditions related to ALOX12B variants are typically inherited in an autosomal recessive pattern. This means an individual must inherit a pathogenic variant from each parent to be affected.
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