ALOX12B – Lamellar Ichthyosis

ALOX12B encodes the epidermal 12R-lipoxygenase (12R-LOX), a non-heme iron dioxygenase critical for ceramide processing and formation of the corneocyte lipid envelope. Biallelic loss-of-function variants disrupt the 12R-LOX/eLOX3 pathway of lipid metabolism in the stratum corneum, leading to impaired barrier function and autosomal recessive lamellar ichthyosis (LI). Gene Symbol variants in ALOX12B underlie a substantial fraction of congenital ichthyosis cases, particularly LI (MONDO:0017778).

Inheritance is autosomal recessive, with compound heterozygous and homozygous mutations reported across diverse populations. Case reports include an African boy presenting with large brown scales and a history of collodion membrane (1 proband) (PMID:16403385), a preterm neonate with ectropium and eclabion (1 proband) (PMID:36854483), and a 2½-year-old with severe dental caries and hypoplastic teeth harboring c.1579G>A (p.Val527Met) (1 proband) (PMID:39917683). A self-healing collodion membrane series described two infants with mild ichthyosis due to compound heterozygous ALOX12B variants (PMID:18347291). In a large cohort of 250 ARCI patients, 21 individuals from 19 unrelated families carried ALOX12B mutations, establishing its frequent involvement in LI and non-bullous congenital ichthyosiform erythroderma (NCIE) (PMID:19131948).

Segregation analysis in multiple families confirms recessive inheritance, with affected sibships segregating pathogenic alleles and unaffected carriers. Variant classes include missense, nonsense, splice-site, frameshift, and in-frame indels, reflecting allelic heterogeneity. Among recurrent alleles, c.1579G>A (p.Val527Met) appears in multiple reports, indicating a possible mutational hotspot in diverse cohorts.

Functional assays demonstrated that patient-derived missense and splice variants abolish 12R-LOX catalytic activity in bacterial and COS7 expression systems (PMID:15629692; PMID:16116617). The ethylnitrosourea-induced “mummy” Alox12b mouse model exhibits perinatal lethality, red scaly skin, defective lamellar granule secretion, and loss of enzyme activity, recapitulating human LI pathology (PMID:17429434).

No conflicting evidence disputing ALOX12B’s role in LI has been reported. Integration of genetic, segregation, and functional data fulfils ClinGen criteria for a definitive gene–disease relationship. Further identification of genotype–phenotype correlations may refine prognostic and therapeutic strategies.

Key Take-home: Biallelic loss-of-function variants in ALOX12B cause autosomal recessive lamellar ichthyosis through disruption of epidermal lipid barrier formation, supporting molecular diagnosis and genetic counseling.

References

• Dermatology online journal • 2005 • Lamellar ichthyosis. PMID:16403385
• BMJ case reports • 2023 • Congenital ichthyosis: a multidisciplinary approach in a neonatal care unit. PMID:36854483
• Frontiers in dental medicine • 2024 • Case Report: Dental treatment under general anesthesia and dental management of a child with congenital ichthyosis. PMID:39917683
• Archives of dermatology • 2008 • Self-healing collodion membrane and mild nonbullous congenital ichthyosiform erythroderma due to 2 novel mutations in the ALOX12B gene. PMID:18347291
• 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
• 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 • 2007 • A mouse mutation in the 12R-lipoxygenase, Alox12b, disrupts formation of the epidermal permeability barrier. PMID:17429434

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