A Mouse Mutation in the 12R-Lipoxygenase, Alox12b, Disrupts Formation of the Epidermal Permeability Barrier  Jennifer L. Moran, Haiyan Qiu, Annick Turbe-Doan,

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A Mouse Mutation in the 12R-Lipoxygenase, Alox12b, Disrupts Formation of the Epidermal Permeability Barrier  Jennifer L. Moran, Haiyan Qiu, Annick Turbe-Doan, Yujuan Yun, William E. Boeglin, Alan R. Brash, David R. Beier  Journal of Investigative Dermatology  Volume 127, Issue 8, Pages 1893-1897 (August 2007) DOI: 10.1038/sj.jid.5700825 Copyright © 2007 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Gross phenotype and histology of newborn mummy mutants. (a–b) mummy mutants are distinguishable from unaffected littermates at birth by their red skin that rapidly desiccates and appears scaly. (c–d) Newborn mummy dorsal skin shows a thickened stratum corneum by hematoxylin and eosin staining of sections (n=9 affected mice; n=10 unaffected mice, evaluated at E17.5, E18.5, and newborn). Bar=150μm. Journal of Investigative Dermatology 2007 127, 1893-1897DOI: (10.1038/sj.jid.5700825) Copyright © 2007 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Genetic mapping and identification of the mummy mutation. (a) The mummy mutation was mapped to a 21Mb interval on Chr 11 between SNPs rs4228770 (58.1Mb) and rs13481117 (79.0Mb) by performing a whole genome scan of 394 SNPs on two parental (A/J × C57BL/6J) F1 and 10 affected F2 progeny. Alleles for the mutated A/J strain (M) are red; C57BL/6J background strain (B), blue; heterozygotes, yellow; and no calls, white. P for parental; U for unaffected and A for affected mice. Genotypes from two nonrecombinant simple-sequence length polymorphism markers, D11Mit29 (69.6Mb) and D11Mit194 (73.2Mb), are also shown. (b) Chromatograms of Alox12b genomic sequence in wild-type A/J (top) and mummy-affected (middle, bottom) mice showing a G to A mutation, which introduces a premature stop codon in mummy mutants. Journal of Investigative Dermatology 2007 127, 1893-1897DOI: (10.1038/sj.jid.5700825) Copyright © 2007 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Reversed-phase HPLC analysis of catalytic activities of wild-type and mutant Alox12b. The His-tagged enzymes expressed in COS7 cells were incubated with [14C]arachidonate methyl ester as substrate and the products analyzed by reversed-phase HPLC using a Waters Symmetry C18 column (25 × 0.46cm) with a solvent system of methanol/water/acetic acid (85:15:0.01, by volume) run at a flow rate of 1ml/minute on an Agilent 2100 series HPLC system equipped with an on-line Flo-One Beta radioactive detector. Arachidonate methyl ester is used as the test substrate because mouse 12R-LOX does not metabolize free arachidonic acid (Krieg et al., 1999). Top trace: profile of unlabeled standards added to the sample before injection and detected with UV recording at 235nm. Middle trace: 14C-labeled products formed by wild-type Alox12b – note that the [14C]12-HETE methyl ester product formed from the [14C]arachidonate methyl ester is mainly hydrolyzed to the free acid by esterase activity in the COS cell extract (cf. ref (Krieg et al., 1999)). Lower trace: 14C elution profile from mutant Alox12b shows no detectable products. Journal of Investigative Dermatology 2007 127, 1893-1897DOI: (10.1038/sj.jid.5700825) Copyright © 2007 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 Analysis of epidermal permeability barrier function in mummy mice. (a) Widespread permeability of X-gal substrate in affected mice at E17.5 (n=5−/−; n=13+/-; n=7−/−) and E18.5 (n=2−/−; n=3 +/-; n=4+/+) compared with littermate controls. (b) The weight of intercross progeny was measured every hour for the first 6hours after birth. Dramatic weight loss of mummy homozygotes at E17.5 and E18.5 (n=5−/−), 21–27% weight loss compared with no more than 3% for control littermates (n=16+/-; n=7+/+), shows a lack of barrier function. Journal of Investigative Dermatology 2007 127, 1893-1897DOI: (10.1038/sj.jid.5700825) Copyright © 2007 The Society for Investigative Dermatology, Inc Terms and Conditions