A mouse mutation in the 12R-lipoxygenase, Alox12b, disrupts formation of the epidermal permeability barrier

J Invest Dermatol. 2007 Aug;127(8):1893-7. doi: 10.1038/sj.jid.5700825. Epub 2007 Apr 12.

Abstract

Nonbullous congenital ichthyosiform erythroderma (NCIE) is a nonsyndromic form of autosomal recessive congenital ichthyosis characterized by hyperkeratosis and a disruption in the epidermal permeability barrier. Identification of mutations in two lipoxygenases (LOXs), ALOX12B (12R-LOX) and ALOXE3 (eLOX3), and further functional studies implicate ALOX12B and ALOXE3 in the etiology of NCIE. Here, we report a mutation in Alox12b in the recessive ethylnitrosurea-induced mouse mutant, mummy (Alox12b(mmy-Bei)). mummy mutants have red, scaly skin and die perinatally. Histologically, mummy mutants display defects in the epidermis. We mapped mummy to a 1.9 Mb interval on Chr. 11 containing Alox12b (12R-LOX), Aloxe3 (eLOX3) and Alox15b (8-LOX). Sequencing of all three genes identified a nonsense mutation in the catalytic domain of Alox12b. We demonstrate that mummy mutants have a disrupted epidermal permeability barrier and that the nonsense mutation in mummy abolishes the enzyme activity of 12R-LOX. The mummy mutant provides a mouse model for LOX-mediated NCIE and is the first described mouse mutant affecting epidermal barrier formation identified by forward genetics.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Arachidonate 12-Lipoxygenase / genetics
  • Arachidonate 12-Lipoxygenase / physiology*
  • Codon, Nonsense*
  • Epidermis / metabolism*
  • Genotype
  • Ichthyosiform Erythroderma, Congenital / genetics*
  • Mice
  • Permeability

Substances

  • Codon, Nonsense
  • Arachidonate 12-Lipoxygenase