ALOX12B – Non-bullous Congenital Ichthyosiform Erythroderma

Autosomal recessive mutations in ALOX12B, encoding 12R-lipoxygenase (12R-LOX), cause non-bullous congenital ichthyosiform erythroderma (NBCIE), a disorder marked by generalized scaling and erythroderma (HP:0000951, HP:0000961). The gene–disease relationship has been validated over >20 years and meets criteria for a Definitive association.

Genetic studies have identified biallelic ALOX12B variants in multiple cohorts, comprising >64 probands across >19 unrelated families (6 families: [PMID:11773004]; 17 families: [PMID:16116617]; 19 families: [PMID:19131948]). Segregation analysis confirms autosomal recessive inheritance in 19 affected relatives.

The variant spectrum includes >25 missense, >10 nonsense, frameshift indels and splice-site mutations, with no recurrent founder alleles described. A prototypical pathogenic change is c.1294C>T (p.Arg432Ter), introducing a premature termination codon.

In vitro assays in E. coli and COS-7 cells demonstrate that both missense and truncating ALOX12B mutations abolish 12R-LOX activity and disrupt hepoxilin synthesis, consistent with loss of function ([PMID:15629692]).

Alox12b knockout (‘mummy’) mice exhibit perinatal lethality, epidermal barrier defects and hyperkeratosis that recapitulate human NBCIE, further supporting causality ([PMID:17429434]).

No conflicting evidence has been reported. Convergent genetic, biochemical and animal model data establish ALOX12B LOF as the basis of NBCIE. Key take-home: Biallelic ALOX12B loss-of-function mutations underlie autosomal recessive NBCIE via impaired epidermal lipid metabolism, informing molecular diagnosis and exploration of lipid-based therapies.

References

• Human molecular genetics • 2002 • Lipoxygenase-3 (ALOXE3) and 12(R)-lipoxygenase (ALOX12B) are mutated in non-bullous congenital ichthyosiform erythroderma (NCIE) linked to chromosome 17p13.1 PMID:11773004
• Human mutation • 2005 • Mutation spectrum and functional analysis of epidermis-type lipoxygenases in patients with autosomal recessive congenital ichthyosis PMID:16116617
• 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
• 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 • 2007 • A mouse mutation in the 12R-lipoxygenase, Alox12b, disrupts formation of the epidermal permeability barrier PMID:17429434

Evidence Based Scoring (AI generated)