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Molecular Analysis of 250 Patients with Autosomal Recessive Congenital Ichthyosis: Evidence for Mutation Hotspots in ALOXE3 and Allelic Heterogeneity in ALOX12B

Division of Dermatogenetics, Cologne Center for Genomics, University of Cologne, Cologne, Germany.
Journal of Investigative Dermatology (Impact Factor: 6.37). 02/2009; 129(6):1421-8. DOI: 10.1038/jid.2008.409
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ABSTRACT In recent years several new genes for autosomal recessive congenital ichthyosis (ARCI) have been identified. However, little is known about the molecular epidemiology and pathophysiology of this genetically and clinically heterogeneous group of severe disorders of keratinization. ARCI is characterized by intense scaling of the whole integument often associated with erythema. We and others have shown that mutations in ALOX12B and ALOXE3, coding for the lipoxygenases 12R-LOX and eLOX-3 predominantly synthesized in the epidermis, can underlie this rare condition. Here we have surveyed a large group of 250 patients with ARCI for mutations in these two genes. We have identified 11 different previously unreported mutations in ALOX12B and ALOXE3 in 21 ARCI patients from 19 unrelated families and demonstrated that mutations in the two genes are the second most common cause for ARCI in this cohort of patients. Examination of the molecular data revealed allelic heterogeneity for ALOX12B and two mutational hotspots in ALOXE3. Functional analysis of all missense mutations and a splice site mutation demonstrated that complete loss of function of the enzymes underlies the phenotype. Our findings further establish the pivotal role of the 12-lipoxygenase pathway during epidermal differentiation.

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Available from: Francisco Martínez, Apr 24, 2014
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    • "Genetic anomalies in the complex physiological process of epidermal barrier formation result in scaly skin diseases (ichthyoses) with medical complications like dehydration, infections, chronic blistering, and rapidcalorie loss [17] [18] [19] [20]. Gene mutations implicated in the autosomal recessive congenital ichthyoses (ARCI) include ALOX12B, ALOX3, CYP4F22, ichthyin and TGM-1 [18,21–24]. "
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    ABSTRACT: This review covers the background to discovery of the two key lipoxygenases (LOX) involved in epidermal barrier function, 12R-LOX and eLOX3, and our current views on their functioning. In the outer epidermis, their consecutive actions oxidize linoleic acid esterified in ω-hydroxy-ceramide to a hepoxilin-related derivative. The relevant background to hepoxilin and trioxilin biochemistry is briefly reviewed. We outline the evidence that linoleate in the ceramide is the natural substrate of the two LOX enzymes and our proposal for its importance in construction of the epidermal water barrier. Our hypothesis is that the oxidation promotes hydrolysis of the oxidized linoleate moiety from the ceramide. The resulting free ω-hydroxyl of the ω-hydroxyceramide is covalently bound to proteins on the surface of the corneocytes to form the corneocyte lipid envelope, a key barrier component. Understanding the role of the LOX enzymes and their hepoxilin products should provide rational approaches to ameliorative therapy for a number of the congenital ichthyoses involving compromised barrier function. This article is part of a Special Issue entitled The Important Role of Lipids in the Epidermis and their Role in the Formation and Maintenance of the Cutaneous Barrier.
    Biochimica et Biophysica Acta 09/2013; DOI:10.1016/j.bbalip.2013.08.020 · 4.66 Impact Factor
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    • "Recent studies suggested a structural role of the 12R-LOX/eLOX-3 pathway via processing of o-hydroxy acylceramides as a prerequisite for the formation of the corneocyte lipid envelope (CLE) (Zheng et al., 2011). Mutations in ALOX12B or ALOXE3 have been detected in B15% of ARCI patients and represent the second most common cause of ARCI (Eckl et al., 2009; Fischer, 2009). Studies of our group and others demonstrated that such mutations may completely abolish the catalytic activity of the respective LOX enzymes (Eckl et al., 2005; Yu et al., 2005). "
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    ABSTRACT: Loss-of-function mutations in the lipoxygenase (LOX) genes ALOX12B and ALOXE3 are the second most common cause of autosomal recessive congenital ichthyosis. The encoded proteins, 12R-LOX and epidermal LOX-3 (eLOX-3), act in sequence to convert fatty acid substrates via R-hydroperoxides to specific epoxyalcohol derivatives and have been proposed to operate in the same metabolic pathway during epidermal barrier formation. Here, we show that eLOX-3 deficiency in mice results in early postnatal death, associated with similar but somewhat less severe barrier defects and morphological changes than reported earlier for the 12R-LOX-knockout mice. Skin lipid analysis demonstrated that the severity of barrier failure is related to the loss of covalently bound ceramides in both 12R-LOX- and eLOX-3-null mice, confirming a proposed functional linkage of the LOX pathway to ceramide processing and formation of the corneocyte lipid envelope. Furthermore, analysis of free oxygenated fatty acid metabolites revealed strongly reduced levels of hepoxilin metabolites in eLOX-3-deficient epidermis, indicating an additional function of eLOX-3 in mammalian skin as a hepoxilin synthase linked to the 12S-LOX pathway.Journal of Investigative Dermatology advance online publication, 26 July 2012; doi:10.1038/jid.2012.250.
    Journal of Investigative Dermatology 07/2012; 133(1). DOI:10.1038/jid.2012.250 · 6.37 Impact Factor
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    • "Two of the three mutations have been previously described in adult patients without the SICI phenotype: p.Arg234X (Jobard et al., 2002) and p.Pro630Leu (Eckl et al., 2005). As ALOXE3 and ALOX12B encode enzymes operating in the same metabolic pathway (Jobard et al., 2002; Brash et al., 2007; Epp et al., 2007) and mutations in both genes are relatively common as causes of ARCI (Eckl et al., 2009; Fischer, 2009), our finding of ALOXE3 mutations in 25% of Scandinavian SICI patients may not be so surprising. Only one of our SICI patients had compound heterozygous TGM1 mutations, confirming a similar rare finding in a German patient (Raghunath et al., 2003). "
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    ABSTRACT: Infants born with autosomal recessive congenital ichthyosis (ARCI) are often encapsulated in a collodion membrane, which shows a lamellar or erythrodermic type of ichthyosis upon shedding. However, some babies show a nearly normal underlying skin after several weeks, a phenotype called "self-healing collodion baby" (SHCB). Mutations in two genes, TGM1 and ALOX12B, have previously been implicated in the etiology of SHCB, but the full genotypic spectrum remains to be determined. DNA sequencing in 11 Swedish and 4 Danish SHCB patients showed ALOX12B mutations in eight cases, ALOXE3 mutations in three cases, and TGM1 mutations in one case. In three patients, we could not find mutations in any of the known ARCI genes. In all cases, a spontaneous shedding of the collodion membrane occurred 2-4 weeks after birth. When re-examined at 2-37 years of age, the patients showed skin xerosis, a mild or focal scaling, palmar hyperlinearity with keratoderma, and a frequent appearance of red cheeks and anhidrosis. Thus, we propose replacing SHCB with the term "self-improving collodion ichthyosis" (SICI). In conclusion, ALOX12B mutations are the leading cause of SICI in Scandinavia, followed by ALOXE3 mutations, which have not been previously associated with this variant of ARCI.
    Journal of Investigative Dermatology 11/2009; 130(2):438-43. DOI:10.1038/jid.2009.346 · 6.37 Impact Factor
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