ALOXE3 – Lamellar Ichthyosis

ALOXE3 encodes epidermal lipoxygenase-3, a key enzyme in the arachidonic acid metabolic pathway required for epidermal barrier formation. Biallelic variants in ALOXE3 underlie autosomal recessive lamellar ichthyosis (MONDO:0017778) characterized by generalized scaling and flexural accentuation. Pathogenic variants cluster on chromosome 17p13 within conserved catalytic domains, leading to defective corneocyte lipid envelope and impaired skin differentiation.

Multiple studies have identified ALOXE3 mutations in ARCI cohorts. A survey of 250 ARCI patients found 11 distinct ALOXE3 alleles in 21 probands from 19 unrelated families ([PMID:19131948]). Independent reports in three consanguineous families confirmed segregation of homozygous or compound heterozygous ALOXE3 variants with disease status ([PMID:26578203], [PMID:26576379]). In total, over 40 probands carrying at least 6 ALOXE3 alleles—including nonsense, missense, splice, and in-frame indels—have been described; c.834C>A (p.Tyr278Ter) recurs as a mutational hotspot ([PMID:16116617]).

Functional assays demonstrate a loss-of-function mechanism. Expression of wild-type and mutant eLOX3 in E. coli and COS7 cells showed that naturally occurring missense and truncating variants abolish hydroperoxide isomerase activity ([PMID:15629692], [PMID:16116617]). Aloxe3-null mice exhibit perinatal lethality with barrier defects and reduced covalently bound ceramides, faithfully modeling the human phenotype ([PMID:22832496]).

No convincing conflicting evidence has been reported that disputes the association of ALOXE3 LoF variants with lamellar ichthyosis.

Together, robust genetic segregation data across ≥19 families and concordant loss-of-function assays in vitro and in vivo establish a strong causal link between ALOXE3 and autosomal recessive lamellar ichthyosis. Key take-home: Biallelic ALOXE3 loss-of-function variants reliably cause lamellar ichthyosis and should be included in ARCI diagnostic panels.

References

• The Journal of investigative dermatology • 2009 • Molecular analysis of 250 patients with autosomal recessive congenital ichthyosis: evidence for mutation hotspots in ALOXE3 and allelic heterogeneity in ALOX12B PMID:19131948
• International journal of dermatology • 2016 • Novel mutations in the genes TGM1 and ALOXE3 underlying autosomal recessive congenital ichthyosis PMID:26578203
• Iranian journal of public health • 2015 • Triallelic Inheritance of TGM1 and ALOXE3 Mutations Associated with Severe Phenotype of Ichtyosis in an Iranian Family - A Case Report PMID:26576379
• Human mutation • 2005 • Mutation spectrum and functional analysis of epidermis-type lipoxygenases in patients with autosomal recessive congenital ichthyosis PMID:16116617
• Biochimica et biophysica acta • 2005 • Mutations associated with a congenital form of ichthyosis (NCIE) inactivate the epidermal lipoxygenases 12R-LOX and eLOX3 PMID:15629692
• The Journal of investigative dermatology • 2013 • Aloxe3 knockout mice reveal a function of epidermal lipoxygenase-3 as hepoxilin synthase and its pivotal role in barrier formation PMID:22832496

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