Non-
bullous congenital ichthyosiform erythroderma (NCIE) is one of the main clinical forms of
ichthyosis. Genetic studies indicated that 12R-lipoxygenase (12R-LOX) or epidermal
lipoxygenase-3 (eLOX3) was mutated in six families affected by NCIE [F. Jobard, C. Lefevre, A. Karaduman, C. Blanchet-Bardon, S. Emre, J. Weissenbach, M. Ozguc, M. Lathrop, J.F. Prud'homme, J. Fischer,
Lipoxygenase-3 (ALOXE3) and 12(R)-lipoxygenase (ALOX12B) are mutated in non-
bullous congenital ichthyosiform erythroderma (NCIE) linked to chromosome 17p13.1, Hum. Mol. Genet. 11 (2002) 107-113.], but the impact of these mutations on LOX function has not been defined. To explore this, we overexpressed the wild-type or mutated
enzymes in E. coli and COS7 cells and then analyzed the essential catalytic properties. We showed recently that human eLOX3 is a
hydroperoxide isomerase (
hepoxilin synthase) that converts the product of 12R-LOX, 12R-hydroperoxyeicosatetraenoic
acid (12R-HPETE) to a specific epoxyalcohol. Using incubations with [(14)C]-labeled substrates and HPLC analyses, we found that the naturally occurring mutations totally eliminate the
lipoxygenase activity of 12R-LOX and the
hydroperoxide isomerase activity of eLOX3. We further demonstrate that the 12R-LOX/eLOX3-derived 8R-hydroxy-11R,12R-epoxide is converted by an
epoxide hydrolase in COS7 cells and in human keratinocytes to a single isomer of 8,11,12-trihydroxyeicosa-5,9,14-trienoic
acid. Taken together, the results support the hypothesis that 12R-LOX, eLOX3, and perhaps an
epoxide hydrolase function together in the normal process of skin differentiation, and that the loss of function mutations are the basis of the LOX-dependent form of NCIE.