ALOXE3 – Non-Bullous Congenital Ichthyosiform Erythroderma

ALOXE3 encodes epidermal lipoxygenase-3 (eLOX3), a hydroperoxide isomerase involved in the terminal differentiation of keratinocytes and formation of the epidermal barrier. Non-Bullous Congenital Ichthyosiform Erythroderma (NBCIE) presents at birth with collodion membrane, generalized scaling, mild erythroderma, and sometimes alopecia (PMID:16403385).

NBCIE is inherited in an autosomal recessive manner. A homozygous nonsense variant c.418C>T (p.Arg140Ter) in ALOXE3 was identified in a patient with NBCIE and Majocchi’s granuloma; his parents were heterozygous carriers (PMID:26370990). Linkage and sequencing in six consanguineous Mediterranean families uncovered ALOXE3 variants including c.367C>T (p.Gln123Ter), c.700C>T (p.Arg234Ter), and c.784+1G>A in six probands (PMID:11773004).

The variant spectrum in ALOXE3 comprises at least 31 loss-of-function alleles (nonsense, frameshift, splice-site) and multiple missense changes across ~47 unrelated patients. A recurrent founder nonsense allele c.2026C>T (p.Gln676Ter) was reported in two Pakistani families (PMID:29935003).

Functional assays in E. coli and COS7 cells demonstrated that all naturally occurring eLOX3 mutants abolish hydroperoxide isomerase activity, confirming loss of function (PMID:15629692; PMID:16116617).

Aloxe3-null mice exhibit perinatal lethality, disrupted epidermal permeability barrier, reduced covalently bound ceramides, and loss of hepoxilin metabolites, recapitulating human NBCIE phenotypes (PMID:22832496).

Clinically, ALOXE3-related NBCIE manifests with scaling, mild erythroderma, collodion membrane at birth, alopecia, and predisposition to dermatophyte infection; early genetic diagnosis enables genetic counseling and antifungal surveillance.

Variants in ALOXE3 have also been proposed in Dravet syndrome and epilepsy but lack replication and mechanistic support outside epidermal dysfunction.

Integration of autosomal recessive inheritance, extensive biallelic variant reports, segregation in consanguineous families, concordant in vitro and in vivo functional data establishes a Strong association between ALOXE3 and NBCIE. Key Take-home: ALOXE3 genetic testing is clinically useful for definitive diagnosis, counseling, and tailored management of NBCIE.

References

• Dermatology online journal • 2005 • Lamellar ichthyosis. PMID:16403385
• International journal of molecular sciences • 2015 • Homozygous ALOXE3 Nonsense Variant Identified in a Patient with Non-Bullous Congenital Ichthyosiform Erythroderma Complicated by Superimposed Bullous Majocchi's Granuloma: The Consequences of Skin Barrier Dysfunction. PMID:26370990
• Human molecular genetics • 2002 • Lipoxygenase-3 (ALOXE3) and 12(R)-lipoxygenase (ALOX12B) are mutated in non-bullous congenital ichthyosiform erythroderma linked to chromosome 17p13.1. PMID:11773004
• Biochimica et biophysica acta • 2005 • Mutations associated with a congenital form of ichthyosis (NCIE) inactivate the epidermal lipoxygenases 12R-LOX and eLOX3. PMID:15629692
• Human mutation • 2005 • Mutation spectrum and functional analysis of epidermis-type lipoxygenases in patients with autosomal recessive congenital ichthyosis. PMID:16116617
• Congenital anomalies • 2019 • Identification and association of recurrent ALOXE3 mutation with non-bullous congenital ichthyosiform erythroderma in two ethnically distinct Pakistani families. PMID:29935003
• 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
• 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

Evidence Based Scoring (AI generated)