Disease relevance of ALOX12B

• We report the identification of mutations in lipoxygenase-3 (ALOXE3) and 12(R)-lipoxygenase (ALOX12B) genes in non-bullous congenital ichthyosiform erythroderma (NCIE) linked to chromosome 17 [1].
• A novel mutation in the 12(R)-lipoxygenase (ALOX12B) gene underlies nonbullous congenital ichthyosiform erythroderma [2].
• 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 [3].
• The human 12R-LOX product, 12R-HETE, appears to be involved in the pathophysiology of psoriasis and other proliferative skin diseases; a role in normal skin development is implied from the spatial and temporal expression patterns of the 12R-LOX in the mouse embryo [4].

High impact information on ALOX12B

• Herein we identify a logical link of the biochemistry to the genetics. eLOX3 functions as a hydroperoxide isomerase (epoxyalcohol synthase) by using the product of 12R-LOX as the preferred substrate [5].
• Here we provide mechanistic evidence for a lipoxygenase route to 12R-HETE in human psoriatic tissue and describe a 12R-lipoxygenase that can account for the biosynthesis [6].
• The 12R-lipoxygenase cDNA is detectable by PCR in psoriatic scales and as a 2.5-kilobase mRNA by Northern analysis of keratinocytes [6].
• Lipoxygenase-3 (ALOXE3) and 12(R)-lipoxygenase (ALOX12B) are mutated in non-bullous congenital ichthyosiform erythroderma (NCIE) linked to chromosome 17p13.1 [1].
• ALOX15B is located in the same orientation 25 kb downstream of ALOX12B, and is composed of 14 exons and 13 introns spanning a total of 9.7 kb of genomic sequence [7].

Biological context of ALOX12B

• Two point mutations and one deletion were found in ALOXE3 and three point mutations were found in ALOX12B in these consanguineous families from the Mediterranean basin [1].
• 12R-lipoxygenase (12R-LOX) and epidermis-type LOX-3 (eLOX-3) are novel members of the multigene family of mammalian LOX [8].

Anatomical context of ALOX12B

• Detection and cellular localization of 12R-lipoxygenase in human tonsils [9].
• In this location the 12R-lipoxygenase might help regulate differentiation of the epithelium or participate in lymphocyte- epithelial cell interactions [9].
• The unexpected appearance of an EST sequence (AA649213) for human 12R-lipoxygenase from germinal center B lymphocytes purified from human tonsils prompted our search for the existence of the enzyme in this novel source [9].
• Here, we present evidence that 12R-LOX and eLOX-3, acting in sequence, and eLOX-3 in combination with another, not yet identified LOX are critically involved in terminal differentiation of keratinocytes and adipocytes, respectively [8].

Regulatory relationships of ALOX12B

• We identified 11 novel point mutations in ALOX12B (one nonsense mutation and 10 missense mutations) and four different inactivating mutations in ALOXE3 [3].

Other interactions of ALOX12B

• RT-PCR analysis demonstrated a predominant expression of ALOXE3, ALOX12B, and ALOX15B in skin [7].
• ALOX15P was found on the opposite DNA strand directly adjacent to the 3'-untranslated region of ALOX12B [7].
• 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 [10].
• Genetic and biochemical evidence suggests a functional link between human 12R-lipoxygenase (12R-LOX) and epidermal lipoxygenase-3 (eLOX3) in normal differentiation of the epidermis; LOX-derived fatty acid hydroperoxide is isomerized by the atypical eLOX3 into a specific epoxyalcohol that is a potential mediator in the pathway [11].

Analytical, diagnostic and therapeutic context of ALOX12B

• A 12R-lipoxygenase in human skin: mechanistic evidence, molecular cloning, and expression [6].
• 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 [10].

References