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

Abstract

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.

Hair Follicular Expression and Function of Group X Secreted Phospholipase A2 in Mouse Skin

“…4, B and C) may be derived mainly from the COX-1/mPGES-1 pathway. The expression levels of epidermal LOXs, including epidermal 12-LOX (Alox12e) and 12R-LOX (Alox12b), abnormalities of which have been shown to be associated with epidermal disorders (50,51), were higher in PLA2G10-Tg skin than in control skin (Fig. 4E), consistent with the epidermal hyperplasia in Tg mice.…”

“…On the basis of these observations, it is likely that the overwhelming majority of PGE 2 signaling may be linked, at least partly, with the hair follicle and epidermal abnormalities observed in PLA2G10-Tg mice. Additionally, coordinated increases in the expression of epidermal-type LOX enzymes, whose mutations or deletions cause epidermal abnormalities such as ichthyosis (50,51), may be associated with epidermal hyperplasia in PLA2G10-Tg mice.…”

Hepoxilin A3 (HXA3) synthase deficiency is causative of a novel ichthyosis form

“…The antibody raised against rat 12S-LOX (HXA 3 synthase) recognized also human epidermal 12S-LOX (HXA 3 synthase). As mutated eLOX3 is still expressed at the protein level in cells [7,8], these findings suggest to us that the patient in the case study has a different ichthyosis form than that reported for NCIE patients, who showed deficiency of 12R-LOX or eLOX3 due to gene mutations [5][6][7].…”

Thematic review series: Skin Lipids. The role of epidermal lipids in cutaneous permeability barrier homeostasis

“…Mutations in either 12R-LOX or eLOX-3 are associated with autosomal recessive congenital ichthyosis (these disorders will be discussed in detail in the review by Peter Elias) (105-107). Both 12R-LOX and eLOX-3 are localized to the differentiated stratum granulosum layer of the epidermis and convert arachidonic acid to hepoxilin-and trioxilin-like compounds that are believed to play a role in regulating keratinocyte differentiation (105,(108)(109)(110)(111). Moreover, very recent studies have shown that the creation of 12R-LOX-deficient mice results in a severe impairment in barrier function, with the mice dying soon after birth from a defective barrier (108).…”