Mutations associated with a congenital form of ichthyosis (NCIE) inactivate the epidermal lipoxygenases 12-LOX and eLOX3

Yu, Zheyong; Schneider, Claus; Boeglin, William E.; Brash, Alan R.

doi:10.1016/j.bbalip.2004.10.007

Cited by 60 publications

(51 citation statements)

References 22 publications

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“…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].…”

Section: Gc-ms Analysissupporting

confidence: 53%

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

et al. 2007

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Non-bullous congenital ichthyosis erythroderma (NCIE) and lamellar ichthyosis (LI) are characterized by mutations in 12R-lipoxygenase (12R-LOX) and/or epidermal lipoxygenase 3 (eLOX3) enzymes. The eLOX3 lacks oxygenase activity, but is capable of forming hepoxilin-type products from arachidonic acid-derived hydroperoxide from 12R-LOX, termed 12R-hydroperoxyeicosa-5,8,10,14-tetraenoic acid (12R-HpETE). Mutations in either of two enzymes lead to NCIE or LI. Moreover, 12R-LOX-deficient mice exhibit severe phenotypic water barrier dysfunctions. Here, we demonstrate that 12R-HpETE can also be transformed to 8R-HXA 3 by hepoxilin A 3 (HXA 3 ) synthase (12-lipoxygenase), which exhibits oxygenase activity. We also presented a novel form of ichthyosis in a patient, termed hepoxilin A 3 synthase-linked ichthyosis (HXALI), whose scales expressed high levels of 12R-LOX, but were deficient of HXA 3 synthase.

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Section: Gc-ms Analysissupporting

confidence: 53%

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

et al. 2007

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“…For example, the deleted region contains a cluster of 3 genes involved in lipid oxygenation, two of which are epidermal lipoxygenases that are expressed primarily in the mouse skin (Boeglin et al ., 1998;Jisaka et al ., 1997;Heidt et al ., 2000). Lipoxygenases have been shown to play important biological roles in mediating adipocyte and skin differentiation, inflammatory responses, and are also expressed in human hair roots (Baer & Green, 1993;Shillabeer et al ., 1998;Furstenberger et al ., 2002;Kantarci & Van Dyke, 2003;Yu et al ., 2003;Yu et al ., 2005). Correlating to this expression pattern, we do see skin phenotypes that include reduction in dermal thickness, subcutaneous adipose layer, hair re-growth potential and skin wound healing in the p53+/m mice, indicating that the loss of these genes may be responsible for this phenotype.…”

Section: S Venkatachalam Department Of Biochemistry and Cellular Anmentioning

confidence: 99%

Complicating the role of p53 in aging

Gentry

Venkatachalam

2005

Aging Cell

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Recently, we described a p53 mutant mouse model (p53+/m mouse model) that presented a paradox, in which tumor free survival was coupled to reduced lifespan instead of extended lifespan (Tyner et al ., 2002). The p53+/m mice expressed a truncated p53 transcript attached to a leader sequence and showed a moderate increase in p53 activity. Based on this data we hypothesized that enhanced levels of p53 caused the early aging and cancer resistance phenotypes. This hypothesis was attractive as it indirectly implied a 'fine tuning' mechanism of tumor suppressor gene expression to maintain homeostasis at the organismal level (Campisi, 2002;Kirkwood, 2002). Our results also lent support to the evolutionary theory of antagonistic pleiotropy that predicts the deleterious effects of tumor-suppressor genes later in life (Williams, 1957). These observations notwithstanding, the p53+/m mouse model presented a caveat, in which tumor free survival was coupled to reduced lifespan instead of extended lifespan. Studies in model organisms have shown that enhanced resistance to oxidative stress correlates with increased longevity (Johnson et al ., 2002;Murakami et al ., 2003). The tumor suppressor functions of p53 overwhelmingly categorize it as a longevity assurance gene and suggest a synergistic effect on lifespan via tumor free survival of the organism. We show that there are 24 genes deleted in the p53+/m mouse model, complicating the role of p53 in aging and raising the possibility that the phenotypes while resembling 'premature aging-like' symptoms, may not be related to the physiological changes seen during normal aging processes.Along with the partial deletion of one of the p53 alleles, the p53+/m mouse had an upstream deletion that was originally not well defined due to the lack of mouse genome sequence data. This undefined deletion was a major drawback for our hypothesis, leaving open the possibility that the loss of other unidentified genes affected the p53+/m phenotypes. The importance of the upstream deletion was further underlined by the fact that we were unable to generate a p53 m/m mouse from p53+/m crosses even though p53 nullizygosity does not lead to embryonic lethality in mice (Donehower et al ., 1992). To determine the extent of the deletion, we blasted the leader sequence (initially cloned along with the truncated p53 transcript) to the Ensembl mouse genome sequence database and found it to be within the Rho guanine exchange factor 15 ( Arhgef15 ) gene approximately 0.6 Mb upstream of p53.To ascertain the fusion of the Argef15 and p53 alleles, we performed Southern blot assays with multiple restriction enzymes that were common to both the alleles. A schematic representation of the wild-type alleles of p53 and Argef15 is shown in Fig. 1 along with the restriction enzyme sites used for the characterization of the breakpoint present in the p53+/m mouse model. As shown in Fig. 2(a,b), the fusion of the two alleles leads to changes in the restriction fragment length polymorphism (RFLP) patterns of the wt and 'm' alle...

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“…Mutations in the lipid transporter protein, ABCA12 cause defective lipid secretion into lamellar granules which then become expelled from the apical surface of keratinocytes [6] as mentioned above and lead to either LI [5] and HI [6,18] phentoypes. Lipoxygenase-3 and 12(R)-lipoxygenase are non-heme iron-containing dioxygenases expressed in the epidermis, and their exact functions are unknown [19,20]. They may be associated with lipid metabolism in the lamellar granule contents and/or intercellular lipid layers in the epidermis.…”

Section: Defective Intercellular Lipid Is the Main Idea Behind The Pamentioning

confidence: 99%

Harlequin ichthyosis and other autosomal recessive congenital ichthyoses: The underlying genetic defects and pathomechanisms

Akiyama

2006

Journal of Dermatological Science

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Mutations associated with a congenital form of ichthyosis (NCIE) inactivate the epidermal lipoxygenases 12-LOX and eLOX3

Cited by 60 publications

References 22 publications

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

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

Complicating the role of p53 in aging

Harlequin ichthyosis and other autosomal recessive congenital ichthyoses: The underlying genetic defects and pathomechanisms

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Mutations associated with a congenital form of ichthyosis (NCIE) inactivate the epidermal lipoxygenases 12-LOX and eLOX3

Cited by 60 publications

References 22 publications

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

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

Complicating the role of p53 in aging

Harlequin ichthyosis and other autosomal recessive congenital ichthyoses: The underlying genetic defects and pathomechanisms

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

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