Spectrum and functional analysis of inactivating mutations in the epidermis-type lipoxygenase genes in autosomal recessive congenital ichthyosis (ARCI). K.M. Eckl1, P. Krieg2, W. Küster3, H. Traupe4, F. André1, N. Wittstruck1, G. Fürstenberger2, H.C. Hennies1. 1) Molecular Genetics and Gene Mapping Center, Max Delbrück Center, Berlin, Germany; 2) Eicosanoids and Tumor Development, German Cancer Research Center, Heidelberg, Germany; 3) Tomesa Fachklinik, Bad Salzschlirf, Germany; 4) Dermatology, University of Münster, Germany.

   Autosomal recessive congenital ichthyosis (ARCI) forms a clinically and genetically heterogeneous group of severe inherited keratinization disorders characterized by intense scaling of the skin, different in color and shape, and often associated with erythema. Mutations in ALOX12B and ALOXE3 on chromosome 17p13, coding for epidermal lipoxygenases 12R-LOX and eLOX-3 preferentially synthesized in the skin, were previously found in patients with ichthyosiform erythroderma. 12R-LOX and eLOX-3 are subsequent members of the same pathway, which converts arachidonic acid to an epoxyalcohol. In a large group of 150 families with ARCI, we identified 20 novel and one previously described point mutations in ALOXE3 and ALOX12B in 20 families from various ethnic backgrounds. We found only few mutations repeatedly in different families but no founder effects as demonstrated by microsatellite analysis. We further analyzed the expression of the mutant genes and developed an in vitro assay in order to determine the enzyme activity using the genuine substrates. Analysis of reaction products by reversed-phase HPLC demonstrated that all missense mutations but one depleted the enzymatic activity of recombinant enzymes. Moreover, we intend to study subsequent changes in the expression of further interacting proteins of keratinocytes. All patients were clinically characterized in detail. We observed that mutations in epidermal lipoxygenase genes resulted in a mild phenotype of ARCI with light scales, normal hair, mild or absent palmoplantar hyperkeratosis, and hypohidrosis. We did not see dark brown scales on the face and/or adherent scales on the trunk. This is the first time that genetic findings in patients with ARCI could be correlated with the phenotype, whereas mutations in the gene TGM1 were seen with the whole spectrum of mild to very severe forms of ARCI.
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