Mutation spectrum and functional analysis of epidermis-type lipoxygenases in patients with autosomal recessive congenital ichthyosis

• Published in: Human mutation Vol. 26; no. 4; pp. 351 - 361
• Main Authors: Eckl, Katja-Martina, Krieg, Peter, Küster, Wolfgang, Traupe, Heiko, André, Françoise, Wittstruck, Nadine, Fürstenberger, Gerhard, Hennies, Hans Christian
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.10.2005; Hindawi Limited
• Subjects: ALOX12B; ALOXE3; Arachidonate 12-Lipoxygenase - genetics; Arachidonate 12-Lipoxygenase - physiology; Catalysis; Chromatography, High Pressure Liquid; Chromosomes; Congenital diseases; congenital ichthyosis; epidermal differentiation; Epidermis - cytology; Epidermis - enzymology; Epidermis - metabolism; Erythema; Genes; Genes, Recessive; genodermatosis; Genomics; genotype/phenotype correlation; hepoxilin; Homozygote; Humans; Ichthyosiform Erythroderma, Congenital - genetics; Ichthyosiform Erythroderma, Congenital - metabolism; lipoxygenase; Lipoxygenase - genetics; Lipoxygenase - metabolism; Lipoxygenase - physiology; Loss of Heterozygosity; Medical research; Microsatellite Repeats; Mutation; Phenotype; Point Mutation; Population Groups - genetics; Protein Structure, Tertiary; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Skin; Germany; Turkey
• ISSN: 1059-7794; 1098-1004
• DOI: 10.1002/humu.20236

Autosomal‐recessive congenital ichthyosis (ARCI) is a clinically and genetically heterogeneous group of severe hereditary keratinization disorders characterized by intense scaling of the whole integument, and differences in color and shape. It is often associated with erythema. To date, six loci for ARCI have been mapped. Mutations in ALOXE3 and ALOX12B on chromosome 17p13, which code for two different epidermal lipoxygenases, were recently found in patients with ichthyosiform erythroderma from Turkey, France, and North Africa. Here we describe molecular and clinical findings in 17 families with ARCI originating from Central Europe, Turkey, and the Indian subcontinent, with mutations in ALOXE3 or ALOX12B. We identified 11 novel point mutations in ALOX12B (one nonsense mutation and 10 missense mutations) and four different inactivating mutations in ALOXE3. The gene products of ALOX12B and ALOXE3, the epidermal lipoxygenases 12R‐LOX and eLOX3, respectively, are preferentially synthesized in the skin. They act in sequence to convert arachidonic acid via 12(R)‐HPETE to the corresponding epoxyalcohol, 8(R)‐hydroxy‐11(R),12(R)‐epoxyeicosatrienoic acid. To assess the impairment of enzyme activity, we expressed the mutated genes in vitro and determined the activity of the recombinant proteins toward their genuine substrates. All but one of the recombinant mutants were enzymatically inactive. The characterization of disease‐causing mutations in ALOXE3 and ALOX12B and the resulting ARCI phenotypes did not result in clear diagnostic criteria; however, we found a first correlation between the genetic findings and the clinical presentation of ichthyosis. Hum Mutat 26(4), 351–361, 2005. © 2005 Wiley‐Liss, Inc.